Medicinal Chemistry in Oncology - CNIO91_booklet.pdfNotes Previous CNIO Cancer Conferences ... 2006 CNIO Cancer Conference: Medicinal Chemistry in Oncology CNIO_005_010_Programmes

CNIO Cancer Conference

Medicinal Chemistryin OncologyMadrid, October 2-4, 2006

Organisers:

Fernando Albericio. Science Park-UB, Barcelona, Spain

James R. Bischoff. Spanish National Cancer Research Centre (CNIO),Madrid, Spain

Carlos García-Echeverría. Novartis Pharma, Basel, Switzerland

Andrew Mortlock. AstraZeneca, Macclesfield, UK

AuditoriumCentro Nacional de Investigaciones OncológicasMelchor Fernández Almagro, 328029 Madrid, Spain www.cnio.es

CNIO_001_004_Contents 27/9/06 09:11 Página 1


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Contents ■

Contents

Programme overview

Detailed Programme

Abstracts-Sessions

Session I: Kinases I 13

Session II: Kinases II 16

Session III: Kinases III 19

Session IV: ATPases 23

Session V: Nuclear Hormone Receptors and Ras Modulators 25

Session VI: Histone deacetylases and poly(ADP-ribose)polymerase 29

Session VII: Antagonists of intracellular protein-protein interactions 32

Session VIII: Case studies 36

Abstracts-PostersIn alphabetical order of presenting author

Invited Speakers’ Portfolio

List of Invited Speakers and Participants

Acknowledgements

Notes

Previous CNIO Cancer Conferences

Forthcoming CNIO Events89

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© Fundación Centro Nacional de Investigaciones Oncológicas Carlos III. Madrid 2006, Spain.Co-ordinated and compiled by Sara Bertrand ([email protected])

Design: Equipo de maquetación de Grafilia, SLPrint: Grafilia, SL


CNIO Cancer Conference in Medicinal Chemistry

Auditorium of the Spanish National Cancer Research Centre, CNIO(Melchor Fernández Almagro, 3, E-28029 Madrid) October 2-4, 2006

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Programme overview ■

Monday, October 2

Welcome address / 09:15h-09:30h

Mariano Barbacid. CNIO Director

I. Kinases I / 09:30h-11:00h

Chair: Carlos García-Echeverría

David J. Matthews. San Francisco (USA)

Laurent Hennequin. Reims (France)

Carlos Garcia-Echeverria. Basel

(Switzerland)

Coffee break and Poster viewing (11:00 - 11:30)

II. Kinases II / 11:30h-13:00h


Andy J Barker. Cheshire (UK)

David Rees. Cambridge (UK)

Alfonso de Dios. Indianapolis (USA)

Lunch (13:00 - 14:30)

III. Kinases III / 14:30h-15:30h


Zachary Knight. San Francisco (USA)

Sonsoles Rodriguez-Aristegui.

Newcastle (UK)

Concepcion Sanchez-Martinez.

Madrid (Spain)


Tuesday, October 3

IV. ATPases / 09:30h-11:00h

Chair: James R. Bischoff

Martin Drysdale. Cambridge (UK)

Paul J Coleman. West Point (USA)


V. Nuclear Hormone Receptors and

Ras Modulators / 11:30h-13:00h


Mark Salvati. Princeton (USA)

Ajay S. Bhatnagar. Muttenz (Switzerland)

María de Luz López Rodríguez. Madrid

(Spain)

Lunch (13:00 - 14:30)

VI. Histone deacetylases and poly(ADP-

ribose)polymerase /14:30h-15:30h


Thomas Miller. Boston (USA)

Keith Menear. Cambridge (UK)


Wednesday, October 4

VII. Antagonists of intracellular

protein-protein interactions /

09:30h-11:00h

Chair: Paolo Pevarello

Christopher Straub. Cambridge (USA)

Shaomeng Wang. Ann Arbor (USA)

Fulvio Gualtieri. Florence (Italy)

Jose Jaen-Oltra. Valencia (Spain)


VIII. Case studies / 11:30h-13:00h

Chair: Paolo Pevarello

Haile Tecle. Cambridge (USA)

Robert M. Borzilleri. Princeton (USA)

Timothy Thomson. Barcelona (Spain)

Kristof van Emelen. Beerse (Belgium)

Final Remarks (13:00)

Note:Talks: 20-minute / Short talk: 10-minuteDiscussion: 10-minute after each talk / 5-minute after each short talk

CNIO_005_010_Programmes 27/9/06 09:18 Página 5

Monday, October 2

09:15 - 09:30 Welcome address, Mariano Barbacid, CNIO Director

Session I: Kinases IChair: Carlos García-Echeverría

09:30 - 10:00 David J. Matthews, Exelixis Inc., South San Francisco, USA

Discovery and Characterization of EXEL-2880 (XL880), an Orally Available Inhibitor ofHGF and VEGF Receptor Tyrosine Kinases

10:00 - 10:30 Laurent Hennequin, AstraZeneca, Centre de Recherches, La Pompelle, Reims, France

Targeting pathological angiogenesis with AZD2171, a novel, potent VEGF receptortyrosine kinase inhibitor

10:30 - 11:00 Carlos Garcia-Echeverria, Novartis Pharma AG, Basel, Switzerland

Blocking IGF-IR kinase activity for cancer treatment

11:00 - 11:30 Coffee break and poster viewing

Session II: Kinases IIChair: Carlos García-Echeverría

11:30 - 12:00 Andy J Barker, AstraZeneca, Alderley Park, Cheshire, UK

Identification of Aurora Kinase Inhibitors for the Treatment of Cancer

12:00 - 12:30 David Rees, Astex Technology, Cambridge, UK

Fragment based CDK Drug Discovery – From Crystal to Clinic

12:30 - 13:00 Alfonso de Dios, Lilly Research Laboratiories, Indianapolis, USA

Development of p38 MAP Kinase inhibitors for Oncology. A new life for an old target

13:00 - 14:30 Lunch

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■ 2006 CNIO Cancer Conference: Medicinal Chemistry in Oncology

Detailed Programme


Session III: Kinases IIIChair: Carlos García-Echeverría

14:30 - 15:00 Zachary Knight, University of California, San Francisco, CA, USA

A chemical map of the PI3-kinase family

15:00 - 15:15 Sonsoles Rodriguez-Aristegui, Northerm Institute for Cancer Research, NewcastleUniversity, Newcastle, UK

Design and synthesis of novel DNA-dependent protein kinase (DNA-PK) inhibitors

15:15 - 15:30 Concepcion Sanchez-Martinez, Lilly, Madrid, Spain

Discovery, synthesis and optimization of Naphthyl[a]pyrrolo[3,4-c]carbazolesas novel D1-CDK4 Inhibitors


Tuesday, October 3, 2006

Session IV: ATPases


09:30 - 10:00 Martin Drysdale, Vernalis, Cambridge, UK

Discovery and Structure Guided Optimisation of Hsp90 Inhibitors for the treatment ofcancer

10:00 - 10:30 Paul J Coleman, Merck Research Laboratories, West Point, USA

Discovery and Optimization of Potent Kinesin Spindle Protein (KSP) Inhibitors


(Short talk selectedfrom posters)


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Detailed Programme ■


Session V: Nuclear Hormone Receptors and Ras ModulatorsChair: James R. Bischoff

11:30 - 12:00 Mark Salvati, Bristol-Myers Suibb Company, Princeton, USA

BMS-591305: A novel [2.2.1]-oxobicyclo based androgen receptor antagonists

12:00 - 12:30 Ajay S. Bhatnagar, Novartis Pharma AG, Muttenz, Switzerland

Development of aromatase inhibitors for the treatment of breast cancer: from the labto the clinic

12:30 - 13:00 María de Luz López Rodríguez, Universidad Complutense de Madrid, Spain

Design and Development of a New Inhibitor of Ras Activation

13:00 - 14:30 Lunch

Session VI: Histone deacetylases and poly(ADP-ribose)polymeraseChair: James R. Bischoff

14:30 - 15:00 Thomas Miller, Merck Research Labs, Boston, USA

Histone Deacetylase Inhibitors

15:00 - 15:30 Keith Menear , KuDOS Pharmaceuticals, Cambridge Science Park, Cambridge, UK

Discovery & Optimisation of Novel Phthalazinone Inhibitors of poly(ADP-ribose)polymerase


Wednesday, October 4, 2006

Session VII: Antagonists of intracellular protein-protein interactionsChair: Paolo Pevarello

09:30 - 10:00 Christopher Straub, Novartis Institute for Biomedical Research, Cambridge, USA

Inhibitors of Apoptosis Proteins: Application of Structure Based Drug Design to theTaming of a Protein-Protein Interaction Target

10:00 - 10:30 Shaomeng Wang, University of Michigan, Ann Arbor, MI, USA

Design and Development of Small-Molecule Inhibitors of the MDM2-p53 Interaction AsA New Class of Anticancer Drugs

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10:30 - 10:45 Fulvio Gualtieri, University of Florence, Florence, Italy

Isomeric N,N-(dicyclohexane-4-ol)amine aryl esters : the discovery of a new classof highly potent and efficacious Pgp-dependent MDR inhibitors

10:45 - 11:00 Jose Jaen-Oltra, Cognitalis, Valencia, Spain

Pharmacoinformatics platform in cancer research. lead optimization


Session VIII: Case studiesChair: Paolo Pevarello

11:30 - 12:00 Haile Tecle, Pfizer Research Technology Center, Cambridge, MA, USA

The Development of Non-ATP Competitive MEK Inhibitors as Potential AnticancerDrugs. PD 0325901: a case study from early screening to the clinical setting

12:00 - 12:30 Robert M. Borzilleri, Bristol-Myers Squibb Pharmaceutical Research Institute,Princeton, USA

The Next Generation of Agents for the Treatment of Philadelphia Chromosome PositiveLeukemias: Discovery of the Dual Src/Abl Kinase Inhibitor Dasatinib (SprycelTM)

12:30 - 12:45 Timothy Thomson, Institut de Biologia Molecular de Barcelona, CSIC, Barcelona, Spain

Chemosensitization of tumor cells by a pharmacological inhibitor of non-canonicalpolyubiquitylation

12:45 - 13:00 Kristof van Emelen, Johnson lab, Beerse, Belgium

The identification of a novel series of N-hydroxybenzamides as potent HDAC inhibitors:synthesis, biological evaluation and structure activity relationships

13:00 Final Remarks





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Detailed Programme ■


List of Posters (in alphabetical order of presenting author)

1 Leticia Cubo - Universidad Autónoma de Madrid, Madrid, SpainSynthesis and Reactivity of Thiosemicarbazones Complexes. Validation as Potential Therapeutic Agents

2 Verónica I. Dodero - Universidad de Santiago de Compostela, Santiago de Compostela, SpainTowards the Preparation of Site-switchable DNA-binding Peptides

3 Olaf Kinzel - IRBM/MRL Rome, Rome, ItalyDevelopment of a Novel Series of Selective Histone Deacetylase Inhibitors with Antitumor Activity In Vivo

4 Fabrizio Manetti - University of Siena, Siena, ItalyNovel tyrosine kinase inhibitors active against a wide panel of tumor cell lines

5 Sonsoles Martín-Santamaría - Universidad San Pablo CEU, Madrid, SpainTwo targets for the discovery of new compounds to fight cancer: matrix metalloproteinases (MMPs),and estrogen receptor (ER).

6 Mariano Martínez Vázquez - Universidad Nacional Autónoma de México, México, D.F., MéxicoSynthesis and comparative molecular fields analysis (CoMFA)of triterpene derivatives as growth inhibitorsof human cancer cell lines

7 María Teresa Molina - Instituto de Química Médica (CSIC), Madrid, SpainDesign, synthesis and antitumor activity of 1,4-anthraquinones and derivatives

8 Cecilia Portela Pallares - Universidad de Santiago de Compostela, Santiago de Compostela, SpainDs-Oligonucleotide-peptide conjugates featuring peptides from the leucine zipper region of c-Fos as anew type of Jun resceptors

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Abstracts-Sessions

CNIO_011_040_Abs_Sessions 27/9/06 09:29 Página 11

Discovery and Characterization of EXEL-2880 (XL880), an Orally AvailableInhibitor of HGF and VEGF Receptor Tyrosine Kinases

David J. Matthews, on behalf of Exelixis Drug Discovery

Exelixis Inc., South San Francisco, CA, USA

Hepatocyte growth factor (HGF) and its receptor (MET) are overexpressed and often activated in a wide varietyof tumor types, promoting tumor growth.Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1/2)are expressed on the surface of vascular endothelial cells, and play a central role in the promotion of tumorangiogenesis. Additionally, HGF and VEGF interact synergistically to promote endothelial proliferation and newblood vessel growth in vivo. Hence, dual inhibition of HGF and VEGF receptors represents a promising newstrategy for treatment of a wide variety of tumors.

EXEL-2880 is a potent inhibitor of MET and VEGFR tyrosine kinase activity, with low nM IC50 values inbiochemical assays. In cell-based assays, EXEL-2880 shows broad antiproliferative activity against a broad panelof tumor cell lines. EXEL-2880 inhibits HGF-induced responses (such as invasion and chemotaxis) in tumor cells,and demonstrates potent anti-angiogenic activity, inhibiting VEGF-induced ERK phosphorylation and in vitrotubule formation in endothelial cells.Treatment with EXEL-2880 in vivo results in dose-dependent and reversibleinhibition of MET and VEGFR2 in pharmacodynamic assays. Following acute administration, EXEL-2880 causesrapid disruption of the tumor vasculature and death of both tumor and endothelial cells. Substantial efficacywas achieved using both daily and intermittent oral dosing in multiple human tumor xenograft models, andimmunohistochemical analysis demonstrated profound inhibitory effects on the tumor vasculature, leading tohypoxia and apoptotic tumor cell death.

In summary, EXEL-2880 demonstrates potent anti-tumor and anti-angiogenic activity in preclinical models andis the first compound targeting HGF and VEGF receptors to enter the clinic. Phase I studies have demonstratedpromising signs of biological and clinical activity, and a phase II study was recently initiated in patients withpapillary renal cell carcinoma.

Session I: Kinases I ■

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Targeting pathological angiogenesis with AZD2171, a novel,potent VEGF receptor tyrosine kinase inhibitor

Laurent F. Hennequin

AstraZeneca, Centre de Recherches, Reims, France

Vascular endothelial growth factor-A (VEGF) is a pivotal stimulus of physiologic and pathologic angiogenesis,including the sustained neovascularisation required to support solid tumour growth.Tumour blood vessels furnishsolid malignancies with oxygen and nutrients, facilitating further dysregulated growth, and provide a route formetastatic dissemination. VEGF signalling is thus an attractive anti-tumour target, given its pivotal role in theregulation of tumour angiogenesis and vascular permeability.

VEGF signals through the endothelial cell receptors VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt-4) byinducing receptor homo- or heterodimerization and stimulating intrinsic tyrosine kinase activity.

AZD2171 is a highly potent ATP competitive inhibitor of recombinant VEGFR-2,VEGFR-1 and VEGFR-3 kinaseactivity in vitro (IC50 values of <1 nM, 5 nM and £3 nM respectively). This compound was selected from a novelseries of indole ether quinazolines. The structure–activity relationship within this series will be described, withadditional reference to the pharmacokinetic and physiochemical properties of these compounds. AZD2171demonstrates excellent selectivity versus a range of tyrosine and serine/threonine kinases that include EGFR,ErbB2, MEK and CDK2 (>1000-fold selectivity when compared with inhibition of VEGFR-2). AZD2171 respectsLipinski’s rules, possessing a low polar surface area (PSA: 82) and a moderate molecular weight. Plasmapharmacokinetic data indicate that AZD2171 has a half-life in rat of 9 hours, low clearance and good oralbioavailability (i.e., F >40%). Once-daily oral dosing of AZD2171 resulted in inhibition of tumour growth in abroad range of human tumour xenografts. Growth of established MDA-MB-231 tumours in athymic mice wasinhibited by 65% and 99% following once-daily administration of 0.75 mg/kg and 3 mg/kg AZD2171 respectively(P<0.001 by one-tailed t-test).

AZD2171 is currently in Phase II and Phase II/III clinical development in patients with advanced malignancies;data from Phase I clinical evaluation will be presented.


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Blocking IGF-IR kinase activity for cancer treatment

Carlos García-Echeverría, J. Brueggen, H.-G. Capraro, D. Fabbro, P. Furet, A. Marti, G. Martiny-Baron,J. Mestan, D. Graus, M.A. Pearson, and F. Hofmann

Novartis Institutes for Biomedical Research, Oncology Research and Global Discovery Chemistry, Novartis Pharma AG,Basel, Switzerland

The Insulin-like Growth Factor I Receptor (IGF-IR) is a transmembrane tyrosine kinase receptor that is activatedby its cognate ligands IGF-I and IGF-II. Upregulation of the receptor, as well as its ligands, has been documentedin several tumor types. Signaling through the IGF-IR activates several downstream pathways that include theGrb2/Sos/Ras/MAPK and the PI-3K/Akt pathways. Thus, IGF-mediated signaling provides both proliferative andsurvival stimuli. IGF-IR has been shown to be essential for both oncogenic transformation and the ability oftumour cells to survive and grow in an anchorage independent manner. Inhibition of IGF-IR signaling by interferingwith its expression or activation has been shown to inhibit tumor growth and metastasis formation in vivo.Conversely, overexpression of this receptor promotes invasion and the formation of metastases.

Among the different approaches explored to block the activation of IGF-IR in cancer cells, the identification ofspecific low-molecular mass kinase inhibitors of IGF-IR has proven to be a major challenge for medicinal chemistrydue to the high sequence identity at the kinase domains of IGF-IR and insulin receptor (InsR). Selectivity overthe InsR is a critical requirement for any IGF-IR kinase inhibitor to avoid disturbing glucose homeostasis. Thispresentation will cover the identification and biological characterization of a new class of potent and cellularlyselective modulators of IGF-IR kinase activity. These new kinase inhibitors, which contain the pyrrolo[2,3-d]pyrimidine scaffold, block IGF-I-dependent IGF-IR autophosphorylation with IC50 values in the low nM range,and, under similar experimental conditions, show 10- to 50-fold selectivity over the native InsR, and weak activityagainst other receptor protein tyrosine kinases. Furthermore, they suppress tumor growth and prolong survivalof mice with diffuse bone lesions of multiple myeloma when used alone or in combination with cytotoxic agents.


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■ 2006 CNIO Cancer Conference: Medicinal Chemistry in OncologySession II: Kinases II

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Identification of Aurora Kinase Inhibitors for the Treatment of Cancer

Andy J Barker

Cancer and Infection Research, AstraZeneca, Alderley Park, Cheshire, UK

Aurora kinases A and B are two closely related serine/threonine kinases that are over-expressed in multipletumour types. The kinases play a key role in cell cycle progression being involved in chromosome segregationand mitosis and represent attractive targets for the treatment of cancer. High throughput screening of a compoundcollection against aurora kinase A identified the aniline-quinazoline pharmacophore as having the potential toselectively and potently inhibit these enzymes. Medicinal chemistry approaches were used to develop the leadsinto compounds having good cellular activity and DMPK properties and a pro-drug strategy provided aqueoussolubility compatible with parenteral dosing. A compound from the class, AZD1152, a selective inhibitor withspecific activity against Aurora kinase B, has been identified to undergo clinical development.


Fragment based CDK Drug Discovery – From Crystal to Clinic

David Rees

Astex Technology, Cambridge, UK

Fragment-based lead discovery is becoming established within pharmaceutical and biotechnology companies asa complementary approach to traditional HTS screening for discovering new chemical leads in drug discoveryprogrammes.1-3 The starting fragments are low molecular weight ligands (MW=120-250) whose binding interactionswith a target protein are structurally understood (eg by X-ray crystallography or NMR) and typically with IC50sin the mM range. This structural knowledge allows the fragments to be progressed into chemical lead serieswith IC50s in the nM range by synthesizing around 20-80 compounds.

Methodology developed at Astex for fragment-based lead discovery utilizes high throughput X-ray crystallography,NMR and other biophysical techniques to screen fragments against various protein targets including kinases,proteases etc. 4-6 The development of multiple oncology lead series using this approach will be outlined fortargets such as cyclin-dependent kinase (CDK), aurora and PKB/Akt. Using this strategy a CDK inhibitor,AT7519,has been progressed from first synthesis to dosing in cancer patients in 18 months.

Attractions of the fragment-based technique include the requirement to screen and synthesise only a fewcompounds and the high success rate of generating multiple chemical series with lead-like properties.

References:

1. Rees, D; Congreve, M; Murray, C; Carr, R; Nature Reviews Drug Discovery, 3, 660-672, 2004.2. Erlanson, D; McDowell, R; O’Brien, T; J. Med. Chem. 47, 3463-3482, 2004.3. Carr, R. Congreve, M; Murray, Rees, D; Drug Discovery Today, 10, 987-992, 2005.4. Gill, A.L. et al., J. Med. Chem. 48, 414-426, 2005.5. Hartshorn, M.J. et al., J Med. Chem. 48, 403-413, 2005.6. Howard, S. et al., J Med. Chem. 49, 1346-1355, 2006.

Session II: Kinases II ■

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Development of p38 MAP Kinase inhibitors for Oncology.A new life for an old target.

Alfonso de Dios

Discovery Chemistry Research and Technologies. Lilly Research Laboratiories. Eli Lilly and Company. Indianapolis, USA

The rational design and discovery of 2-aminobenzimidazole-based series of potent p38α MAP Kinase inhibitorswill be presented along with binary Xray crystallography data and detailed chemistry SAR. Lead compound inthis series showed Ki = 5 nM, ATP competitive binding affinity and low nanomolar activity in the inhibition ofTNFα release in LPS-stimulated macrophages. It was also found that this chemical class selectively inhibits MK2phosphorylation in vitro in stimulated macrophages. Broader kinase profiling showed that our lead compoundin this series presented a remarkable selectivity.

Lead optimization was aimed to overcome both metabolic instability and Cyp3A4 liability.This SAR strategy ledto a breakthrough improvement in rat plasma exposure, oral bioavailability and half life that correlated withimproved in vivo activity. In this manner, an optimized lead molecule showed highly desirable PK/PD propertiesand efficacy in preclinical efficacy models for rheumatoid arthritis.

Additional opportunities were explored for this chemical series in the Oncology area. Careful selection ofcytokine dependent tumor models was followed by development of pMK2 in vivo inhibition assays to evaluatep38 activity in solid tumors. Advanced compound LY2322600 showed potent suppression of pMK2 formationand remarkable tumor growth inhibitory effect in combination with DNA alkylating agents in U87MG humanglioblastoma xenograft models. LY2322600 significantly induced chemopotentiation of DNA alkylating agentseffect in this model after 2 cycles of treatment.

Although the mechanistic basis for the observed chemopotentiation has not been elucidated yet, our data clearlyindicates that inhibition of macrophage-derived p38a by a highly selective p38 inhibitor may prevent tumorgrowth by disrupting the tumor microenvironment and tumor-host interactions. Additional work is in progressto understand the role and potential applications of p38 MAP Kinase inhibitors for Oncology indication.

References:

1. de Dios, A. et al. J. Med. Chem. 2005, 48, 2270-2273.2. Schultz, R. M. Progress in Drug Research, 2003, 60, 59-92.3. Starling, J. et al. American Association for Cancer Research 2006. Book of abstracts p 575, presentation # 2429.


Session III: Kinases III ■

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A chemical map of the PI3-kinase family

Zachary Knight

University of California, San Francisco, CA, USA

Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles ofPI3-K isoforms remain poorly defined. I will describe a chemical approach to study signaling by PI3-K isoforms.A chemically diverse panel of PI3-K inhibitors was synthesized and their target selectivity was biochemicallyenumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitorsbound to p110gamma revealed conformationally mobile regions that are uniquely exploited by potent andselective compounds.The role of these regions in inhibitor binding was validated through the design of resistantalleles and inhibitor analogs. This chemical array was then used to explore insulin signaling by PI3-K isoforms.We found that p110alpha is the primary insulin-responsive PI3-K in fat and muscle, whereas p110beta isdispensable, but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha blocked theacute effects of insulin treatment in vivo, whereas p110beta inhibitors had no effect. These results reveal adominant role for p110alpha in growth factor signaling and suggest a rationale for the selective mutation of thisisoform in cancer.


Design and synthesis of novel DNA-dependent protein kinase (DNA-PK) inhibitors

Sonsoles Rodriguez-Aristegui a, Marine Desage-El Murra, Bernard T. Goldinga, Roger J. Griffina,Ian R. Hardcastlea, Caroline Richardsonb, and Graeme C. M. Smithb

a) Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, University of Newcastle-upon-Tyne, UK.

b) KuDOS Pharmaceuticals Limited, Cambridge Science Park, Cambridge, UK

The nuclear serine/threonine kinase DNA-dependent protein kinase (DNA-PK), a member of thephosphatidylinositol 3-kinase-like kinase (PIKK) family, comprises a large catalytic subunit (DNA-PKcs) and aheterodimeric subunit (Ku). DNA-PK detects DNA double-strand break (DSB) formation, and initiates damagerepair by mediating the non homologous end-joining (NHEJ) pathway.[1] DSBs are produced by ionising radiationand certain cancer chemotherapeutic agents, and DNA-PK inhibition has been shown to potentiate the in vitrocytotoxicity of ionising radiation and a number of anticancer drugs. Our studies have centred on the developmentof potent and selective DNA-PK inhibitors, suitable for clinical evaluation as agents to enhance the cytotoxicityof DNA-damaging anticancer therapies.

Using LY294002 (1) (IC50= 1.2 ?M), and our recently developed selective DNA-PK inhibitor NU7441 (2, R= H) (IC50= 12 nM)[2] [3] as templates, we wished to study modifications to the core pharmacophore, includingreplacement of the chromen-4-one scaffold by the isochromen-1-one (isocoumarin) structure (3). To thisend, efficient synthetic routes have been developed to prepare isocoumarins that retain the essential 3-morpholinyl group, and vary with respect to the 5-aryl substituent (R). In addition, the effect, upon biological


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activity, of substitution on the dibenzothiophene ring of NU7441 (2, R = H) was investigated, through thesynthesis of novel analogues bearing a variety of groups at the 6´-, 7´- and 8´-positions (2, R = Cl, OMeetc). The synthesis and biological activity of the target isocoumarin and novel chromen-4-one DNA-PKinhibitors will be discussed.

References:

1. Smith, G. C.; Jackson, S. P. Review. Genes & Development, 1999, 916-934.2. Leahy, J.J.J.; Golding, B.T.; Griffin, R.J.; Hardcastle, I.R.; Richardson, C.; Rigoreau, L.; Smith, G.C.M.. Bioorg. Med. Chem. Lett.,

2004, 14, 6083-6087.3. Hardcastle, I. R.; Cockcroft, X.; Curtin, N. J.; Desage El-Murr, M.; Leahy, J. J. J.; Stockley, M.;. Golding, B. T.; Rigoreau, L.;

Richardson, C.; Smith, G. C. M; Griffin, R. J. J.Med.Chem., 2005, 48, 7829-7846.


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Discovery, synthesis and optimization of Naphthyl[a]pyrrolo[3,4-c]carbazoles asnovel D1-CDK4 Inhibitors

Concepción Sanchez-Martinez1, C. Shih2, T. Li2, M. M. Faul2, T. Engler2, M. Paal3, G. Zhu2, C. A. Kumrich2,L. L. Winneroski2, J. L. Grutsch2, J. T Cooper2, S. P. Kolis2, F. Zhang2, H. B. Brooks2, B. K. R. Patel2, R. M. Schult2,T. B. DeHahn2, C. D. Spencer2, S. A. Watkins2, E. Considine2, J. A. Dempsey2, C. A. Ogg2, R. M. Campbell2,B. A. Anderson2, J. Wagner2, S. Conner

(1) Lilly Spain, Madrid, Spain(2) Lilly Research Laboratories, Indianapolis, USA (3) Lilly Forschung GmbH Hamurg, Germany

The Cyclin-Dependent Kinases (CDKs) play important role in regulating the cellular division, transcription anddifferentiation. The G1, S, G2 and M phases of the cell division cycle are controlled by different CDK/cyclinpairs. In particular, the D type cyclins associate with CDK4 and 6 are believed to play a critical role in the G1check point and the CDK/cyclin activities are frequently deregulated in many cancer types. Novelnaphthyl[a]pyrrolo[3,4-c]carbazoles are found to be potent CDK4 inhibitors. These pyrrolocarbazoles are ATPcompetitive inhibitors for CDK4 and exhibit antiproliferative activities against several human tumor cell lines invitro. The specific G1 cell cycle arrest and selective inhibition of phosphorylation of serine 780 on pRb areconsistent with the D1-CDK4 inhibitory activity. Synthesis, kinase selectivity profile and structure-activityrelationship of these naphthyl[a]pyrrolo[3,4-c]carbazoles will be described.


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Discovery and Structure Guided Optimisation of Hsp90 Inhibitors for thetreatment of cancer

Martin J. Drysdale

Vernalis, Cambridge, UK

Heat shock protein (Hsp) 90 is a molecular chaperone that is responsible for the correct folding of a largenumber of proteins allowing them to achieve their functional conformation. Client proteins of Hsp90 includemany key overexpressed or mutated oncogenes which are known to be critical for the transformed phenotypeobserved in tumors. 17-AAG and 17-DMAG are Hsp90 inhibitors derived from the prototypical ansamycinnatural product inhibitor geldanamycin, which have shown pre-clinical efficacy in mouse xenograft models, andare now in phase I and II clinical trials. Our own efforts in the optimization of a class of Hsp90 inhibitorsdiscovered simultaneously by medium throughput screening and using the Vernalis proprietary computationalvirtual screening platform rDock, will be described.

Session IV: ATPases ■

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Discovery and Optimization of Potent Kinesin Spindle Protein (KSP) Inhibitors

Paul J. Coleman, Christopher D. Cox, John D. Schreier, Michael J. Breslin, George D. Hartman, Rob Lobell,Carolyn Buser, Weikang Tao, Hans Huber, and Nancy Kohl.

Merck Research Laboratorios, Departments of Medicinal Chemistry and Cancer Research, West Point, PA, USA

Mitotic kinesin motor proteins are involved in bipolar spindle assembly, maintenance and elongation, chromosomealignment and segregation, and microtubule depolymerization, among other functions during cell division. Kinesinspindle protein (KSP, also known as Eg5) is a mitotic kinesin that is essential for proper separation of spindlepoles during mitosis. Disruption of KSP function results in collapse of bipolar spindles and gives rise to monopolarspindle arrays, referred to as monoasters. This characteristic phenotype is accompanied by cell cycle arrest inmitosis, and prolonged mitotic arrest in tumor cells can lead to apoptosis. KSP inhibitors therefore may havepotential as general antiproliferative agents useful for the treatment of cancer. Additionally, KSP inhibitionrepresents a novel and specific mechanism by which to target the mitotic spindle that may be devoid of theneuropathy-associated, mechanism-based side effects common to the taxanes and other natural products thattarget microtubules. In this presentation, we will describe the discovery and optimization of small molecule KSPinhibitors derived from a 3,5-diaryl-4,5-dihydropyrazole high-throughput screening lead. We will show how thisscreening lead was modified and refined with regard to potency, pharmacokinetics, and suitability for aqueousformulation. In this presentation, we will discuss how physicochemical properties were carefully managed inorder to minimize P-glycoprotein efflux and off-target ion channel activities.


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BMS-591305: A novel [2.2.1]-oxobicyclo based androgen receptor antagonists

Mark Salvati, Ricardo Attar, Aaron Balog, Marco Gottardis, Stanley Krystek, Richard Rampulla,Dacia Pickering, Soren Giese, Weifeng Shan, Donna Wei, Hong Zhu, Arvind Mathur, Jieping Geng, Cheryl Rizzo,Maria Jure-Kunkel, Janet Dell, Thomas Spires, Dan Kukral

Bristol-Myers Suibb Company, Discovery Oncology Department, Princeton, USA

Prostate cancer (CaP) is the 2nd leading cause of cancer related deaths in men, claiming 37,000 lives in 1999.Androgen ablation is the gold standard treatment for advanced CaP, with non-steroidal antagonists of theandrogen receptor (AR) playing an increasing role in this treatment regiment. Currently, all androgen ablationtherapy is palliative with 50% of all patients advancing to androgen refractory CaP within 18 months. In acontinuation of our efforts to find antagonists of the AR, we progressed our novel series of [2.2.1]-bicyclic imidebased AR antagonists. Through iterative design and testing, we identified a novel series of [2.2.1]-oxobicyclobased AR antagonists. Analysis of key analogs in this series revealed a unique pharmacological profile in vivorelative to other known AR antagonists.

Session V: Nuclear Hormone Receptors and Ras Modulators ■

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Development of aromatase inhibitors for the treatment of breast cancer: fromthe lab to the clinic

Ajay S. Bhatnagar

World Wide Services Group Ltd., Muttenz, Switzerland

Estrogen deprivation is effective therapy for the treatment of hormone responsive breast cancer.This cornerstoneof endocrine therapy in breast cancer has been developed over the last 100 years starting with the observationby Beatson that ovariectomy led to an anti-tumor response in a woman with breast cancer. Since then, seminalfindings relating to the biosynthesis of estrogens, the mechanism of action of estrogens and the characterizationof the enzyme aromatase which is the crucial last step in estrogen biosynthesis, have shown us that agentswhich block the estrogen receptor (like the anti-estrogen tamoxifen) or block estrogen biosynthesis (like thearomatase inhibitor letrozole) are effective in treating breast cancer.

For over 2 decades, tamoxifen has been considered to be the “gold standard” in the treatment of breast cancer.Today, the 3rd generation aromatase inhibitors are directly challenging the supremacy of tamoxifen through a varietyof clinical trials across the entire spectrum of breast cancer therapy.The 3rd third generation AIs available commerciallyfor the treatment of breast cancer are letrozole (Femara®), anastrozole (Arimidex®) and exemestane (Aromasin®).

Since tamoxifen is an anti-estrogen and has a different mechanism of action than the AIs, the studies mentionedabove have as their end-point, anti-tumor efficacy in breast cancer. However, since AIs all have the same mechanismof action, they can be directly compared with each other in their ability to inhibit aromatase. It is now welldocumented that a large proportion of breast tumors express their own aromatase which produces estrogenin situ and therefore may contribute significantly to the amount of estrogen to which the cell is exposed. Thusit is not only important that aromatase inhibitors potently inhibit the peripheral production of estrogen andthus eliminate the external supply of estrogen to the tumor cell, but that they also potently inhibit intracellulararomatase and thus prevent in situ production of estrogen. To study the inhibition of both peripheral andintracellular aromatase we have compared the aromatase-inhibiting potency of letrozole and anastrozole in avariety of model endocrine and tumor cellular systems which contain aromatase. Results from these studieswill be presented as will results from clinical studies designed to test whether the differences between the AIsseen in the cellular studies are reflected in the clinical setting.

Clinical trials involving all of the third generation AIs have either been completed or are on-going againsttamoxifen, the gold standard for the treatment of hormone-responsive breast cancer. Published results fromthese trials, which have been conducted in both advanced disease and in the adjuvant setting in breast cancer,will be compared and contrasted in an attempt to reveal if any differences exist between the AIs in their abilityto effectively treat breast cancer.


Design and Development of a New Inhibitor of Ras Activation

María Luz López Rodríguez

Universidad Complutense de Madrid, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Madrid, Spain

The extensive involvement of mutated Ras in the development of numerous cancers supports the idea that thepharmacological modification of Ras function could open up new opportunities for the development of innovativeantitumoral therapies1. In this context, and in collaboration with the pharmaceutical company Exonhit Therapeutics,we have focused on the search of compounds able to inhibit Ras activity by direct interaction with the protein.

Using high-throughput screening techniques EHT-0459 was identified as a lead compound. Based on this structure,different libraries of compounds2 considering structural modifications in the aromatic ring, the spacer and thepyranone system were synthesized and the impact on Ras signalling pathways was analyzed in the presence ofconstitutively activated Ras (RasVal12). A three-dimensional quantitative structure-affinity relationship study(3-D-QSAR), using the comparative molecular field analysis (CoMFA), has been applied and compound EHT-0229was designed and synthesized as an optimum derivative.

EHT-0229 induces cytotoxicity in four tumoral cell lines (HTC116, H460, MDA231 and MCF7) in a selectivemanner against non tumoral cell lines (MCF10A, NIH3T3 and MRC-5), and displays its cytotoxic effect in thepresence of constitutively activated Ras (RasVal12). Mechanistically, this compound disrupts actin architectureand specific features of tumor cells such as anchorage-independent growth and invasion. Besides, administrationof EHT-0229, either in acute or chronic form, does not induce any toxic effect in mice.


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Using saturation transfer difference (STD) and tr-NOESY NMR techniques, the complex between EHT-0229 andRas protein has been characterized. Taking into account these NMR results a computational simulation of thecomplex has been proposed.

Beyond these compelling results, some important points that would confirm the feasibility of this approach asa valid therapeutic strategy are to unequivocally determine the binding site of the inhibitor and to establish theactual effect of the compound in relevant in vivo tumoral models. Hopefully all these efforts will translate intonovel approaches that provide new pharmacological tools in the fight against cancer.

Acknowledgments: This work was supported by ExonHit Therapeutics and Ministerio de Educación y Ciencia(SAF2004-07103).

References:

1. Walker, K.; Olson, M. F. Curr. Opin. Genet. Dev. 2005, 15, 62.

2. (a) López-Rodríguez, M. L.; Viso, A.; Leblanc, V.; Melle, D.; Leblond, B. Patente US 6552073 B1, 2003.(b) Leblanc, V.; Leblond, B.; Melle, D.; López-Rodríguez, M. L.; Viso, A.; Beausoleil, E.; Picard, V.; Piñar, M. C.; Teverne, T.Patente PCT WO03/074508A1, 2003.


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Session VI: Histone deacetylases and poly(ADP-ribose)polymerase ■

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Histone Deacetylase Inhibitors

Thomas A. Miller

Merck Research Labs, Boston, USA

Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are currently under clinicalinvestigation.The results from these studies indicate that HDAC inhibitors show great promise for the treatmentof cancer. Since the identification of potent naturally occurring HDAC inhibitors in the 1990’s, several naturalproducts and a multitude of synthetic inhibitors have been identified through screening and rational design.HDAC inhibitor lead structures have provided effective platforms for further optimization and created designparadigms that have afforded HDAC inhibitors with sub-nanomolar enzyme inhibitory activities. Hydroxamicacids constitute the largest chemical class of HDAC inhibitors and these agents are among the most potentHDAC inhibitors known.Additional HDAC inhibitor chemical classes include benzamides, cyclic peptides, carboxylicacids and electrophilic ketones. The discovery and development of novel HDAC inhibitors, along with relevantbackground information, will be discussed in detail.



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Discovery & Optimisation of Novel Phthalazinone Inhibitorsof poly(ADP-ribose)polymerase

Keith Menear

KuDOS Pharmaceuticals, Cambridge Science Park, Cambridge, UK

PARP-1 activation is an immediate cellular response to metabolic, chemical or ionising-radiation induced DNAdamage. Studies have shown that inhibition of PARP-1 activity enhances the effects of certain classes ofchemotherapeutics as well as ionising-radiation indicating the potential for PARP-1 inhibition as a combinationtherapy in oncology.

Moreover, recent studies have shown that in certain genetic backgrounds tumour cells are extremely sensitiveto the effects of PARP-1 inhibition without the need for the presence of a cytotoxic agent leading to selectivecell death. For example BRCA1 and BRCA2, which are components of the homologous recombination DNArepair pathway, are deleted in 5-10% breast cancer patients and we have shown that PARP-1 inhibitors are ahighly effective monotherapy in this setting. These results indicate that for cancer treatment PARP inhibitors,whether as agents for combination with chemotherapies or as potential monotherapies, could be of significanttherapeutic importance.

Previous investigators have designed inhibitors of PARP-1 to mimic the substrate-protein interactions of NAD+

with the enzyme. Mechanistically, these compounds inhibit PARP-1 by blocking the binding of the substrate,particularly the nicotinamide moiety, to the active site of the enzyme. Early weak inhibitors such as 3-aminobenzamide have been developed into more potent PARP-1 inhibitors derived from a range of relatedpharmacophoric templates. The presentation discusses our own work on the development and optimisation ofa novel series of 4-benzylphthalazinones as potent inhibitors of PARP-1.

High throughput screening of the Maybridge Screening Collection, backed by structure-based design utilising ahomology model derived from the known crystal structure of chicken PARP-1, identified several 4-aryl-2H-phthalazinones as low micromolar PARP-1 inhibitors.

Development of this key pharmacophore has lead to the discovery of a number of enzymatic and cellularlypotent PARP-1 inhibitors. Further lead optimisation focussed primarily on enhancement of pharmacokineticproperties has afforded orally available PARP-1 inhibitors for use either in combination with existing cytotoxicsor as a monotherapy in target tumour types.


References

1. Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.; Kyle, S.; Meouth, M.; Curtin, N., J.; Helleday, T.Nature 2005, 434, 913.

2. Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D. A.; Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.;Knights, C.; Martin, N. M. B.; Jackson, S. P.; Smith, G. C. M.; Ashworth, A. Nature 2005, 434, 917.

3. Vincent M. Loh, Jr,. Xiao-ling Cockcroft, Krystina J. Dillon, Lesley Dixon, Jan Drzewiecki, Penny J. Eversley, Sylvie Gomez,Janet Hoare, Frank Kerrigan, Ian T. W. Matthews, Keith A. Menear, Niall M. B. Martin, Roger F. Newton, Jane Paul, GraemeC. M. Smith, Julia Vile and Alan Whittle. Bioorganic & Medicinal Chemistry Letters 2005, 15, 2235-2238.

4. Xiao-ling Cockcroft, Krystyna J. Dillon, Lesley Dixon, Jan Drzewiecki,Vincent M. Loh, Jr., Frank Kerrigan, Keith A. Menear,Niall M.B. Martin and Graeme C.M. Smith. ..Bioorg. Med. Chem. Lett. (2006), 16 (4), 1040-1044.


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■ 2006 CNIO Cancer Conference: Medicinal Chemistry in OncologySession VII: Antagonists of intracellular protein-protein interactions

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Inhibitors of Apoptosis Proteins: Application of Structure Based Drug Design tothe Taming of a Protein-Protein Interaction Target

Christopher S. Straub, Sushil K. Sharma, Leigh Zawel, Kirk Clark, Sid Topiol

Novartis Institute for Biomedical Research, Department of Oncology, Cambridge, Massachusetts, USA

Apoptosis signaling networks ultimately converge on individual Caspases, which, once activated, cleave a numberof cell death-related substrates, effecting destruction of the cell.Tumor cells have devised a number of strategiesto circumvent apoptosis. One recently reported molecular mechanism involves the overexpression of membersof the IAP family. IAPs sabotage apoptosis by directly interacting with and neutralizing Caspases. The prototypeIAPs, XIAP and cIAP have three functional domains referred to as BIR 1, 2 & 3 domains. BIR3 domain interactsdirectly with Caspase 9 and inhibits its ability to bind and cleave its natural substrate, Procaspase 3.

A proapoptotic mitochondrial protein, Smac, is capable of neutralizing IAP’s by binding to a peptide bindingpocket on the surface of BIR3 thereby precluding interaction between IAP’s and Caspase 9. An initial high-throughput screen seeking inhibitors of XIAP failed to produce any lead compounds. As such we began ourefforts to find effective inhibitors by minimizing the Smac protein to a 3-mer peptide, then examining scaffoldsto further optimize a drug candidate. Utilizing structure based drug design we have considered and synthesizedseveral peptidomimetic scaffolds which exhibit good in vitro activity in multiple tumor cell lines. In addition toshowing strong single agent activity these compounds also demonstrate strong synergy when combined withseveral cytotoxics against a broader panel of cell lines. This activity translated well in in vivo models of humancancer, displaying disease stasis or regression when administered alone, and enhancing the efficacy of other anti-cancer agents in these tumor models. In all cases these compounds were well tolerated. This presentation willdetail the design efforts of this program and will highlight the evolution of a drug like small molecule from anatural ligand in this protein-protein interaction target.


Session VII: Antagonists of intracellular protein-protein interactions ■

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Design and Development of Small-Molecule Inhibitors of the MDM2-p53Interaction As A New Class of Anticancer Drugs

Shaomeng Wang

Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan ComprehensiveCancer Center, Ann Arbor, MI, USA

The p53 tumor suppressor plays a central role in controlling cell cycle progression, DNA repair and apoptosisand is an attractive cancer therapeutic target because its tumor suppressor activity can be stimulated to eradicatetumor cells. In approximately 50% of human tumors, p53 retains its wild-type status but its activity is inhibitedby its endogenous cellular inhibitor, the human MDM2 onco-protein. Inhibition of MDM2 can therefore effectivelystimulate the p53 activity in p53 wild-type cancer cells to eradicate tumor cells.Targeting the MDM2-p53 protein-protein interaction using non-peptide small-molecule inhibitors is being pursued as a new and promising therapeuticapproach for anticancer drug design.

Using a computational structure-based strategy, our laboratory has designed a class of highly potent, non-peptide,small-molecule inhibitors of the MDM2-p53 interaction based upon a natural product scaffold. Our most potentsmall-molecule inhibitors have a binding affinity of 1-5 nM to MDM2, >1000-times more potent than the naturalp53 peptide. They are highly effective and specific in inhibition of cell growth and induction of apoptosis incancer cells with wild-type p53 and show no or minimal toxicity to normal cells. Our extensive in vitro and invivo mechanism studies clearly show that our potent small-molecule inhibitors of the MDM2-p53 interactionhave a molecular mechanism of action consistent with targeting the interaction between MDM2 and p53. Ourmost promising lead compounds are highly effectively in inhibiting tumor growth in multiple xenograft modelsof human cancer with wild-type p53. Our studies demonstrate that non-peptide small-molecule inhibitors ofthe MDM2-p53 interaction have the great therapeutic potential to be developed as an entirely new class ofanticancer drugs for the treatment of many type of human cancer retaining wild-type p53.


Isomeric N,N-(dicyclohexane-4-ol)amine aryl esters : the discovery of a newclass of highly potent and efficacious Pgp-dependent MDR inhibitors

Elisabetta Teodoria, Cecilia Martellia, Dina Manettia, Silvia Deia, Maria Novella Romanellia, Serena Scapecchia,Milena Salernob, Arlette Garnier-Suillerotb, Fulvio Gualtieria

a) Dipartimento di Scienze Farmaceutiche, Università di Firenze, Firenze, Italy.b) Laboratoire de Physicochimie Biomoléculaire et Cellulaire Université Paris, Paris, France

Multidrug resistance is a kind of acquired drug resistance of cancer cells to structurally and mechanisticallyunrelated chemotherapic drugs (1). Classical MDR (2 )is associated with accelerated efflux of the chemotherapic,as a consequence of the expression of proteins acting as extrusion pumps (Pgp, MRP13).Direct information on their structure are scarce(4-6) but they point to the existence of a large, polymorphousdrug recognition domain, where a variety of molecules can be accommodated in a plurality of binding modes.(7,8)Inhibition of the functions of Pgp, is considered an approach to circumvent MDR; drugs possessing inhibitoryproperties are actively being sought (9-12) but no drug has been approved for therapy, yet.(13,14)As a follow up of previous research (10,15) we have designed a new series of molecules with a N,N-dicyclohexylamine scaffold that can originate four geometrical isomers with different shape. We will describeand discuss new, fairly potent and efficacious inhibitors of Pgp-dependent MDR, with unprecedented low-nanomolar activity.

References

1. Mitscher, L. A. et al., Med. Res. Rev. 1999, 19, 477.2. Volm, M et al.,. Crit. Rev. Oncogenesis 1996, 7, 227.3. Aszalos, A. et al., Anticancer Res. 1998, 18, 2937.4. Rosenberg, M. F. et al., J. Mol. Pharmacol. 2004, 66, 1332.6. Rosenberg, M. F. et al., EMBO J. 2004, 23, 2923.8. Yu, E. W. et al., Science 2003, 300, 976.9. Teodori, E. et al., Farmaco 2002, 57, 385.

10. Teodori, E. et al., Curr. Drug Targets 2006, 7, 893.11. Avendano, C. et al., Curr. Med. Chem. 2002, 9, 159.12. Robert, J. et al., J. Med. Chem. 2003, 46, 4805.13. Hodgkinson, R. et al., Expert Opin. Invest. Drugs 2002, 11, 1023.14. Sorbera, L. A. et al., Drug Future 2003, 28, 125.15. Teodori, E. et al., J. Med. Chem. 2005, 48, 7426.


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35

Pharmacoinformatics platform in cancer research: lead optimization

Jose Jaen-Oltra

Cognitalis, Valencia, Spain

The purpose is to optimize the molecules or compounds that demonstrate the potential to be transformedinto drugs, increasing the potency and specificity, improving the absorption, distribution, metabolism and excretion(ADME) and diminishing the toxicity.

Computational methods are increasingly used to streamline and enhance the lead discovery and optimizationprocess.These methods are being applied as early in the drug discovery value chain as possible to achieve earlyattrition of unpromising candidate compounds. Models based on chemical structure are strengthened by in vitroresults that can be used as additional compound descriptors to predict complex in vivo endpoints. However,accurate prediction of all factors is often difficult, due to the complexity of underlying physiological mechanismsand by the lack of robust and standardized training datasets.

The development of the pharmacoinformatics platform utilizes tens of thousands of compounds for evidenceof the ability to inhibit the growth of 59 human tumor cell lines, representing leukemia, melanoma and cancersof the lung, colon, brain, ovary, breast, prostate, and kidney from the In Vitro Cell Line Screening Project (IVCLSP)a dedicated service providing direct support to the Developmental Therapeutics Program (DTP), an anticancerdrug discovery program of the National Cancer Institute (NCI).

To illustrate current trends in drug discovery, an integrated in silico platform is presented. The Cognitalispharmacoinformatics platform represents a systematic effort to accelerate the process of drug discovery.


The Development of Non-ATP Competitive MEK Inhibitors as PotentialAnticancer Drugs. PD 0325901: a case study from early screeningto the clinical setting

Haile Tecle

Pfizer Research Technology Center, Cambridge, MA, USA

Tyrosine kinase receptors and many other mitogenic receptors on cell surface, initiate a signal that is transmittedto the nucleus via a series of phosphorylations of the RAS-RAF-MEK-ERK signal transduction pathway.The signalis an absolute prerequisite for proliferation in most cell types. Hyperactivation of this signal transduction pathwaydue to overexpression of tyrosine kinase receptors or mutation in RAS is the cause for a large number ofproliferative diseases including cancer. MEK inhibitors, therefore, have the potential for a broader spectrum ofantitumor activity than agents that inhibit only one portion of the tumor?s redundant proliferative pathways.

MEK forms a tight complex with ERK prior to phosphorylating it. MEK is highly specific for the phosphorylationof ERK; no other substrate for MEK is known. MEK phosphorylates ERK on tyrosine Y185 and threonine T183.Both tyrosine and threonine must be phosphorylated for ERK to be fully activated. These unique attributes ofMEK suggest that selective MEK inhibitors may be found. To this end we screened our compound libraries forMEK inhibitors and discarded any structures remotely resembling those of known ATP-competitive kinaseinhibitors from the hit list. Subsequent SAR work lead to CI-1040, our first generation MEK inhibitor to reachthe clinic. CI-1040 was withdrawn from further development due to insufficient efficacy in Phase II trials. Oursecond generation MEK inhibitor, PD-0325901, like CI-1040, is a non-ATP competitive MEK inhibitor. It is 200-fold more soluble than CI-1040, ca. 500-fold more potent than CI-1040 in cellular assays and significantly morepotent in our in vivo animal tumor models than CI-1040. PD-0325901 is currently in Phase II clinical trials. SARand pre-clinical pharmacology of CI-1040/PD-0325901, Phase I/II results for CI-1040, Phase I results for PD-0325901 and. the x-ray structure of MEK will be discussed.

■ 2006 CNIO Cancer Conference: Medicinal Chemistry in OncologySession VIII: Case studies

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Session VIII: Case studies ■

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The Next Generation of Agents for the Treatment of Philadelphia ChromosomePositive Leukemias: Discovery of the Dual Src/Abl Kinase Inhibitor Dasatinib(SprycelTM).

Robert M. Borzilleri, Francis Y. Lee, Ping Chen, Derek Norris, Joel C. Barrish, Kamelia Behnia, Amy Camuso,Stephen Castaneda, Lyndon A. M. Cornelius, Jagabandhu Das, Arthur M. Doweyko, Krista Fager, ChristineFlefleh, Craig Fairchild, John T. Hunt, Ivan Inigo, Kathy Johnston, Amrita Kamath, David Kan, Herbert Klei,Roger Luo, Punit Marathe, Suhong Pang, Russell Peterson, Sidney Pitt, Gary L. Schieven, Robert J. Schmidt,John Tokarski, Mei-Li Wen, Robert Wild, John Wityak and Louis J. Lombardo

Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

Imatinib mesylate (GleevecTM) is currently first-line therapy for patients with Philadelphia chromosome positive(Ph ) human chronic myelogenous leukemia (CML), a hematological stem cell disorder driven by the constitutivelyactive protein tyrosine kinase (PTK) Bcr-Abl. Although imatinib provides durable responses in newly diagnosedCML and Ph acute lymphoblastic leukemia (ALL) patients, relapses have been observed particularly in patientswith advanced stages of the disease.Various mechanisms have been proposed to account for the resistance toimatinib, such as: (1) point mutations in the kinase domain of Bcr-Abl, (2) overexpression of the Bcr-Abl PTK,(3) Bcr-Abl independence, and (4) activation of alternative oncogenes, including members of the Src-family ofnon-receptor PTKs.We have recently identified substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)-thiazole-5-carboxamides as potent dual Src/Abl kinase inhibitors with excellent antiproliferative activity against solidtumor and hematological cell lines. Moreover, the orally bioavailable, 2-aminopyrimidinyl derivative dasatinib(SprycelTM) retains activity in several clinically relevant imatinib-resistant cell lines and provides complete tumorregressions at multiple dose levels in wild-type and imatinib-resistant in vivo tumor models of CML. Consistentwith these preclinical findings, dasatinib demonstrated significant hematologic and cytogenetic response rates inCML and Ph ALL patients with resistance or intolerance to imatinib. Crystallographic analysis of dasatinib boundto the Abl kinase domain suggests that the increased binding affinity of dasatinib relative to imatinib may beattributed to the ability of the agent to recognize multiple conformations of Bcr-Abl. The crystal structure alsoprovides mechanistic rationale for the ability of dasatinib to overcome all known imatinib-resistant Bcr-Ablmutants, except for the T315I variant. In addition to the structure-activity relationships, preclinical pharmacologyand structural biology supporting the selection of dasatinib for clinical development, a brief survey of additionalsmall-molecule Bcr-Abl inhibitors that have progressed to various stages of development, including those thatmay circumvent the elusive T315I mutation, will be discussed.


Chemosensitization of tumor cells by a pharmacological inhibitor of non-canonical polyubiquitylation

Johanna Scheper1, Marta Guerra-Rebollo1, Glòria Sanvicens2, Alejandra Moure2, Domingo González3,Núria Rubio4, Bernat Crosas1, Noureddine Loukili1, Vanessa Plans1, Antonio Morreale3, Jerónimo Blanco4,Angel R. Ortiz3, Àngel Messeguer2, and Timothy M. Thomson1*

1 Department of Molecular and Cellular Biology, Institut de Biologia Molecular de Barcelona, Consejo Superior deInvestigaciones Científicas, Barcelona, Spain

2 Department of Biological Organic Chemistry, Institut d’Investigacions Químiques i Ambientals de Barcelona, ConsejoSuperior de Investigaciones Científicas, Barcelona, Spain

3 Bioinformatics Unit, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Consejo Superiorde Investigaciones Científicas, Madrid, Spain

4 Centro de Investigación Cardiovascular, Consejo Superior de Investigaciones Científicas, Barcelona, Spain

The heterodimeric ubiquitin conjugase UBC13-UEV catalyzes non-canonical polyubiquitylation that uses Lys63of the ubiquitin protein to form isopeptide bonds between ubiquitin moieties. Modification by Lys63-basedpolyubiquitylation modulates the activities of proteins that exert key functions in DNA repair, signaling, endocytosisand cell motility. By applying in vivo screenings of a chemical combinatorial library and computational optimization,we have developed small molecules that efficiently compete with UEV for its interaction with UBC13 and inhibitits enzymatic activity in vitro and in vivo. In the yeast Saccharomyces cerevisiae, these compounds mimic deltaubc13 phenotypes. In mammalian cells, they inhibit NFkappa-B signaling and sensitize tumor cells to chemotherapeuticagents. One of these compounds, designated Varubin, significantly potentiated the inhibition by doxorubicin ofprostate tumor cell xenograft growth in nude mice. This is the first development of pharmacological inhibitorsof non-canonical polyubiquitylation, and the first demonstration that these compounds produce significantbiological effects with potential therapeutic applications.


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The identification of a novel series of N-hydroxybenzamides as potent HDACinhibitors: synthesis, biological evaluation and structure activity relationships

Kristof van Emelen, Janine Arts, Patrick Angibaud, Hans de Winter, Virginie Poncelet, Ann Marien,Sven van Brandt, Wim Floren, Marc Verdonck, Jacky van Dun, Tamara Geerts, Leo Backx, Boudewijn Janssens,Isabelle Pilatte, Bruno Roux, Jacky van Gompel, Michel Carpentier, David Corens, Lieven Meerpoel,Peter Hellemans, Eddy Freyne and Michel Janicot

Johnson lab, Department of Medicinal Chemistry, Beerse, Belgium

Histone deacetylases (HDACs) represent a family of enzymes that compete with histone acetyltranferases (HATs)for modification of the nucleosomal histone proteins. Histone acetylation status modulates chromatin structureand thereby regulates transcriptional activity of a subset of genes.

Aberrant reduction in acetylation due to disruption of HDAC or HAT activity is associated with the developmentof cancer. Deregulated, sustained HDAC recruitment to the chromatin is observed in specific forms of leukaemiaand lymphoma, such as APL and non Hodgkin?s lymphoma. In agreement with a key role of HDAC activity incancer, HDAC inhibitors from various structural families induce histone hyperacetylation, activate gene expressionand consequently, inhibit the cell cycle, activate differentiation programmes or induce apoptosis. HDAC inhibitorshave been described to exhibit potent anti-tumor activity in human xenograft animal models, suggesting thatthis class of compounds represents promising novel cancer therapeutic agents.

We have identified novel N-hydroxybenzamides showing potent HDAC inhibition and culminating in theidentification of R306465 (JNJ16241199) as a nanomolar HDAC inhibitor with anti-tumor activity when dosedorally in human xenograft-bearing nude mice.

In this contribution, the strategy, synthesis and pharmacological and preclinical evaluation leading to the identificationof R306465 will be discussed in detail.

R306465 is currently undergoing Phase I clinical trials.


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Abstracts-Posters

CNIO_041_050_Abs_Posters 27/9/06 10:24 Página 41


Synthesis and Reactivity of Thiosemicarbazones Complexes. Validation asPotential Therapeutic Agents

Leticia Cuboa Adoración G. Quirogaa Victoria Moneob Amancio Carnerob and Carmen Navarro-Ranningera

a) Inorganic Chemistry Department, Universidad Autónoma de Madrid. Spainb) Experimental Therapeutics Programme, CNIO, Madrid, Spain.

Organometallic complexes have recently attracted attention as potential anticancer agents.1 Our studies usinga thiosemicarbazone (TSCN) as ligand and Palladium (II) and Platinum (II) as metals ions resulted in differentcomplexes:2 tetranuclear complexes where orthometallation has been produced in the ortho position of theligand, dinuclear complex is a chloro-bridged complex where the ligand do not afford orthometallation, andmononuclear complexes with two chloro leaving groups. In this poster presentation we show the last resultswith a new TSCN with nitro substituents.The results achieved for this new TSCN has rendered new complexesthat supports the mechanism postulated on how cyclometallation reaction takes place. Platinum complexesderivate from this ligand, showed high cytototoxic values (micromolar range) in following tumoral cells. MCF-7, NCI-H460, and SF268. The crystal structure of the new potential antitumor metal compound, [PtL1(L1H)] isalso reported.

Acknowledgement: We would like to thank the Ministerial Spanish Research program SAF-03-1700.

References:

1. Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105, 2527-2571.

2. Quiroga, A. G. and Navarro-Ranninger, C. Coord. Chem. Rev. 2004, 248, 119-133.

Abstracts-Posters ■

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1


Towards the Preparation of Site-switchable DNA-binding Peptides

Verónica I. Dodero, Juan B. Blanco and José L. Mascareñas

Departamento de Química Orgánica, Universidad de Santiago de Compostela, Spain

Cells receive a wide variety of cellular and environmental signals which must be processed to generate specificand timely genetic responses. This process is controlled to a large extent at the level of gene transcription.Studies on various model systems have shown that a relatively small number of transcription factors can setup strikingly complex spatial and temporal patterns of gene expression. [1] This is possible because the DNArecognition capabilities can be regulated in a stimuli-responsive combinatorial manner [2].

With the goal of mimicking such combinatorial DNA recognition our current work is being focused towardsthe preparation of peptides that can be delivered to different DNA addresses in an externally switchable manner.The work uses as reference the well known yeast transcriptional activator protein GCN4 that achieves anexquisite recognition of specific DNA sequences by means of a homodimeric bZIP motif.We plan to synthesizesimpler peptide analogues of the basic region of the natural GCN4 equipped with functionalities allowingdimerization through the C- or N-terminal extremity and thereby modulating the recognition of different DNAbinding sites. [3]

References

1. Identifying regulatory networks by combinatorial analysis of promoter elements. Y. Pilpel, P. Sudarsanam, G.M ChurchNat. Genet 29, 153?159 (2001).

2. Building transcriptional regulatory complexes: signals and surfaces. K.R Yamamoto, B.D Darimont, R.L Wagner, J.AIniguez-Lluhi Cold Spring Harb Symp Quant Biol 63, 587?598 (1998).

3. For previous work of our group in the design of DNA-binding peptides, see: From Transcription Factors to DesignedSequence-specific DNA-Binding Peptides. M. E. Vázquez, A. M. Caamaño, J.L. Mascareñas Chem. Soc. Rev. 32, 338-349(2003).


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2


Development of a Novel Series of Selective Histone Deacetylase Inhibitors withAntitumor Activity In Vivo

O. Kinzel*, S. Altamura, F. Colaceci, O. Gonzalez Paz, R. Ingenito, G. Mesiti, G. Pescatore, A. Petrocchi, M.Rowley, R. Scarpelli, C. Steinkühler, P. Jones

IRBM/MRL Rome, Italy

HDAC inhibitors have emerged as promising therapeutics for many diseases, in particular for cancer where severalcompounds are in late stage clinical trials. Histone deacetylases (HDACs) are enzymes that are involved in theepigenetic regulation of gene expression. They catalyze the deacetylation of lysine residues on proteins, mainly onhistones. HDAC inhibition causes hyperacetylation of histones which leads to a more open chromatin structure,thereby facilitating gene transcription and ultimately leading to differentiation, growth arrest and apoptosis. Overexpressionof HDACs and abnormal regulation of histone acetylation has been demonstrated in a number of human tumors.

Most known HDAC inhibitors target the majority of the 11 class I and II HDAC isoforms. In an effort to identifya 2nd generation compound with an improved therapeutic window, a project was started to find a class I-selective HDAC inhibitor.

Apicidin is a potent cyclic tetrapeptide HDAC inhibitor identified at Merck in the mid 1990?s, containing aunique alkyl ketone as a zinc binding group. Directed screening of the compound collection for structurescontaining similar long alkyl ketones identified lead compound IRBM-1. It shows inhibition of HDACs in thenanomolar range in vitro and inhibits tumor cell growth at low micromolar concentrations.

This poster will describe the evolution of IRBM-1 into IRBM-2, a selective HDAC inhibitor with potentantiproliferative activity against multiple cancer cell lines. Data will be presented demonstrating that IRBM-2 isefficacious in an HCT116 xenograft model and displays an improved toxicity profile.


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Novel tyrosine kinase inhibitors active against a wide panel of tumor cell lines

Silvia Schenone, Chiara Brullo, Marina Ziche, Sandra Donnini, Fabio Carraro, Antonella Naldini, Giovanni Maga,Giada Locatelli, Adriano Angelucci, Mauro Bologna, Annalisa Santucci, Adriano Spreafico, Fabrizio Manetti,Marco Radi and Maurizio Botta

Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy

In the last decade, the most explosive advances in the field of cancer therapy have been seen in the area ofprotein Tyrosine Kinases (TKs).

Recently our research group has patented novel pyrazolo[3,4-d]pyrimidine derivatives (general abbreviation: SI)which showed higher activity on different tumor cell lines with respect of PP2 taken as reference compound[1]. These compounds were found to block Src phosporylation, induce apoptosis and reduce cell proliferationboth in hepidermoid carcinoma (A431 cells) and breast cancer (8701-BC cells) [2]. Moreover, the same compoundsdemonstrated a strong effectiveness in blocking tumor cell adhesion, migration and proliferation in prostatecancer (PC3 cells) [3]. Recently, the activity of these pyrazolo[3,4-d]pyrimidines on malignant osteoblasts (suchas the osteosarcoma SaOS-2 cell line) has been also evaluated resulting in a selective reduction of tumor cellsgrowth while did not inhibit normal osteoblasts [4]. SI molecules have also shown to be not toxic at cellularlevel and consequently they represent interesting candidates for further development. In addition, a computationalprotocol based on a pharmacophoric model has been recently used for the identification of dual Src/Abl tyrosinekinase inhibitors endowed with a new scaffold, some of which also showed appreciable selectivity [5].

References:

1. Bondavalli, F.; Botta, M.; Bruno, O.; Manetti, F.; Schenone, S.; Carraro, F. 2004, WO 2004/106340.

2. Carraro, F.; Naldini, A.; Pucci, A.; Locatelli, G. A.; Maga, G.; Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Brullo, C.;Fossa, P.; Menozzi, G.; Mosti, L.; Modugno, M.; Tintori, C.; Manetti, F.; Botta, M. J. Med. Chem. 2006, 49, 1549-1561.

3. Angelucci, A.; Schenone, S.; Gravina, G. L.; Muzi, P.; Festuccia, C.; Vicentini, C.; Botta, M.; Bologna, M. Eur. J. Cancer 2006(accepted for publication).

4. Botta, M. et. al, (submitted for publication).

5. Manetti,F.; Locatelli, G. A.; Maga, G.; Schenone, S.; Modugno, M.; Forli, S.; Corelli, F.; Botta, M. J. Med. Chem. 2006, 49,3278-3286.


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Two targets for the discovery of new compounds to fight cancer: matrixmetalloproteinases (MMPs), and estrogen receptor (ER).

M. A. García, S. Martín-Santamaría, J. J. Rodríguez, A. Martínez, A. Ramos and B. de Pascual-Teresa.

Universidad de San Pablo CEU, Departamento de Química, Madrid, SpainInstituto de Neurobiología Ramón y Cajal, CSIC, Madrid, Spain

Two targets are presented for the discovery of new compounds to fight cancer: matrix-metalloproteinases(MMPs), and estrogen receptor (ER).

Inhibition of various MMPs has been an active area of research for the past 30 years. [Ann. N.Y. Acad. Sci. 1999,878, 388-403] A large number of potent inhibitors have been discovered and some have been tested in clinicaltrials as therapies for cancer with great expectations. On the other hand, taking into account experimentalevidences, it has been proposed that positive modulators of adrenomedullin (AM) may increase AM biodisponibility.Also, it has been shown that AM is specifically degraded by MMP type 2 (MMP-2). [Martínez, A. et al. Biochem.J. 2004, 383, 1?6] Therefore, we have postulated that positive modulators synthesized by us (see Other Information)could act as inhibitors of MMP-2. Our theoretical studies have shown that all compounds were able to bindMMP-2 active site, and form stable complexes with the protein, interacting with the catalytic zinc and, interestingly,with some key aminoacids described as responsible for MMP-2 selectivity. Preliminary experimental results arein complete agreement with our theoretical predictions, showing that at least one compound is a moderateMMP-2 inhibitor (microM range).

Selective Estrogen Receptor Modulators (SERMs) have shown interesting applications in the treatment andprevention of breast cancer. [Breast Cancer Res., 2004 6, 39-52] We are currently working on the design andsynthesis of new series of non steroidal compounds as potential SERMs, following a synthetic strategy basedon a photochemical electrocyclic reaction. Simultaneously, antiproliferative assays and computational studies onthe mode of binding of these compounds to the ERs subtypes are being carried out, in order to design newstructures with an increased affinity and selectivity. At this moment, we have a newly designed molecule with apromising antiproliferative profile against T47D cells.

AM is a peptidic hormone isolated in 1993, whose function is related to several diseases such as diabetes,hypertension and cancer. [Julián, Cacho, García, Martín-Santamaría, de Pascual-Teresa, Ramos, Martínez, Cuttita.Eur. J. Med. Chem. 2005, 40, 737-750] A HTS carried out at the National Cancer Institute (NCI), detected someAM positive modulators that showed an interesting hypotensive activity.A recent synthetic and 3D-QSAR studyhas been carried out with a series of related compounds. [Garcia, Martin-Santamaria, Cacho, de la Llave, Julian,Martinez, de Pascual-Teresa, Ramos. J. Med. Chem. 2005, 48, 4068-4075


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Synthesis and comparative molecular fields analysis (CoMFA)of triterpenederivatives as growth inhibitors of human cancer cell lines

Hortensia Parra-Delgado(1), César M. Compadre(2), Teresa Ramírez-Apan(1), Patricia Ostrosky-Wegman(3)

and Mariano Martínez Vázquez(1).

(1) Instituto de Química, Universidad Nacional Autónoma de México, México(2) Departament of Pharmaceutical Sciences University of Arkansas for Medical Sciences, USA(3) Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México

Synthesis, characterization, anticancer activity, and comparative molecular field analysis (CoMFA) of 14 argentatinB analogs are described.The effect of argentatin B derivatives on the growth of K562 (leukemia), PC-3 (prostate),U251 (CNS), and HCT-15 (colon) human cancer cell lines was determined using the sulforhodamine B test.Themost active compound in this series, 2- formyl-(16 β,24R)-16,24-epoxy-25-hydroxycycloart-1-en-3-one (12), wasabout 35–50 times more potent than argentatin B (1). Structures were built using the X-ray crystallography ofsix derivatives for 3D modelling with Sybyl6.9. CoMFA of Log (1/IC50) in K562 cell line gave q2 = 0.507, r2 =0.907, and three components.The standard deviation CoMFA contours indicate that increased activity is associatedwith a bulky group at C-2, a C1–C2 double bond, and low electronic density at C-25. Experimental LogP valuesfor argentatin B and one derivative were 1–2 Log units more hydrophilic than the calculated CLogP values.


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Design, synthesis and antitumor activity of 1,4-anthraquinones and derivatives

María Teresa Molina(a), Sandra Taliansky(a), Honghao Sun(a), Amancio Carnero(b), Fernando Blanco(b),María Victoria Moneo(b), Beatriz García(b)

(a) Instituto de Química Médica (CSIC), Madrid, Spain(b) Departamento de Terapias Experimentales (CNIO), Madrid, Spain

We have prepared a number of quinonoid compounds, in particular, different series of 1,4-anthraquinone derivativesand we have measured their cytotoxic properties against a range of tumor cell lines.Although 9,10-anthraquinonesare very well known in antitumor therapy (ametantrone, mitoxantrone), 1,4-anthraquinones have been scarcelystudied and we have prepared a diverse set of compounds with this structural motif. Regarding antitumor activity,the few antecedents concerning 1,4-anthraquinones refer compounds only substituted at position 6 (1).

In our work we cover a broader range of substituents and in higher number of positions. Thus, we havesynthesized 2- and 3-substituted alkylquinones and their corresponding epoxides. The epoxides underwent ringopening reactions with a variety of anhydrides leading to different diesters. On the other hand, different 2- and3-chloro- and bromo derivatives, and similar dihalo derivatives of 1,4-anthraquinone were prepared, which byreaction with a number of nucleophiles gave rise to an array of quinone haloethers and amino derivatives(monoamino-, chloroamino-, bromoamino- and diamino-1,4-anthraquinones)

The products were preliminary tested against 6 tumor cell lines: sarcoma (CNIO-AA), prostate cancer (PC-3),breast cancer (MCF-7), lung cancer (A-549 and NCI- H460) and Central Nervous System (SF-268). Somecompounds inhibited cellular growth in most of the tested lines and others were selective against one of them,the activity being in the micromolar range (2). IC50 were calculated for the most active compounds identifiedin the preliminary assays, using HeLa cells, SAOS-2, U2OS, H1299, and 293T tumor cell lines with someconcentrations being in the low nanomolar range (5-10nM). Some haloderivatives proved the most active in thestudy.

References:

1. D. H. Hua, K. Lou, J. Havens, E. M. Perchellet, Y. Wang, J.-P. Perchellet,T. Iwamoto. Tetrahedron 2004, 60 ,10155

2. M. T. Molina, H. Sun, S. Taliansky, A. Carnero, F. Blanco, M.V. Moneo, B. García. Span. Pat. Appl. 200502145 (CSIC, CNIO).


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Ds-Oligonucleotide-peptide conjugates featuring peptides from the leucinezipper region of c-Fos as a new type of Jun resceptors

Cecilia Portela, Ramón Eritja, Fernando Albercio, José Luis Mascareñas

Departamento de Química Orgánica, Universidade de Santiago de Compostela, SpainInstituto de Biología Molecular de Barcelona, CSIC Barcelona, SpainInstitut de Recerca Biomèdica, Parc Científic de Barcelona, Spain

The nuclear oncoproteins Fos and Jun are members of the well known family of transcription factors that bindspecific DNA sequences by means of a bZIP motif. It is well known that these proteins are overexpressed ina variety of cancers and proliferative diseases and therefore there is a great interest in antagonizing their activity.

Our studies focused on the construction of ds-oligonucleotide-peptide conjugates that can selectively target theoncoprotein Jun, owing to the presence of a bivalent binding surface provided by the peptide and the dsDNA.

Herein, we describe the synthesis of covalent conjugates between dsDNA and a 35-aminoacid peptidic regionof the hydrophobic leucine region of c-Fos and demonstrate that these synthetic dsDNA-peptide constructsexhibit better c-Jun sequestrating properties than either the oligonucleotide or the peptide as isolated entities.


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Invited Speakers’ PortfolioA compilation of short scientific biographies of organisers and speakers in accordancewith the order of the programme

CNIO_051_070_SpeakersPort 27/9/06 13:13 Página 51


53

David J. Matthews, Ph.D. is SeniorDirector of Oncology Discove-

ry at Exelixis, Inc. He was previouslyDirector of Structural Biology atExelixis, and prior to this heldvarious positions at other biotechno-logy/pharmaceutical companies in theSan Francisco bay area. Dr. Matthewsreceived a Ph.D. in biophysics fromImperial College, University ofLondon, England and completed hispostdoctoral training in the ProteinEngineering department at Genen-tech, Inc.

David J. Matthews, Ph.D.Senior Director, Oncology DiscoveryExelixis Inc.South San Francisco, CA, USA



54

Laurent F Hennequin received hisundergraduate degree in Chemis-

try in 1982 from Rouen Universityand a PhD in Organic Chemistryfrom the Rouen University in 1986.He was a Postdoctoral Fellow atColumbia University in the labora-tory of Professor Gilbert Stork in1986-1987.

Laurent F Hennequin joinedAstraZeneca in Reims (France) in1988 where he specialised in DrugDesign working on antibacterialresearch programs. In 2001, hemoved to AstraZeneca UK andstarted specialising in the field ofCancer Research working on targetssuch as Thymidylate Synthase andADEPT (Antibody-Directed-Enzyme-Prodrug-Therapy). He then led DrugDesign programs at AstraZeneca in

the field of angiogenesis (inhibitionof the VEGFR tyrosine kinase) andinvasion (inhibition of the c-Srckinase).

Laurent F Hennequin is author ofnumerous publications and patentsin these fields.

Laurent F Hennequin is currentlySenior Principal Scientist andDirector of Chemistry. He is alsoHead of the French Cancer andInfection Discovery unit of AstraZeneca.

Laurent F Hennequin, Ph.D.Senior Principal Scientist and Director of Chemistry andHead of the French Cancer and Infection Discovery UnitCancer & Infection Research DepartmentAstraZenecaReims, France



55

Dr Carlos Garcia-Echeverriareceived his Ph.D. degree in

organic chemistry at the Universityof Barcelona under the supervisionof Prof. Fernando Albericio and Prof.Miquel Pons. After a 3-year post-doctoral stay at the University ofMadison-Wisconsin with Prof. DanielRich, he joined the ExploratoryResearch Unit of Ciba-Geigy (nowNovartis Institutes for BioMedicalResearch) in 1993, and the OncologyResearch Group in 1995. He hasbeen the medicinal chemistrysponsor and team head of differentprograms involving tumor cellgrowth control and apoptosis.Recently, he has been appointedExecutive Director – OncologyDrug Discovery. His research acti-vities have been mainly focused on

the identification and developmentof inhibitors of protein and lipidkinases, proteolytic enzymes, andantagonists of intracellular protein-protein interactions. He is aninventor on 20 patents (issued orpending), and has published 10 bookchapters and more than 100 articlesand review papers. He has beenhonored with the Novartis LeadingScientist Award (2002), the NovartisOncology President’s Award (2003)and the Leonidas Zerwas Award(2006). He is Senior Editor ofChemical Biology & Drug Desig, anda board member of Drug DesignReviews-Online, Expert Opinion onTherapeutic Targets, Journal ofPeptide Research and Therapeutics,and Recent Patent Reviews on Anti-cancer Drug Discovery.

Carlos Garcia-Echeverria, Ph.D.Executive Director - Oncology Drug Discovery Novartis Institutes for BioMedical Research Basel, Switzerland


■ 2006 CNIO Cancer Conference: Medicinal Chemistry in OncologySession II: Kinases II

56

Andy studied for his first degreeat Nottingham University and

went on to undertake a PhD insynthetic organic chemistry at thesame university working with Prof.Gerry Pattenden. Following post-doctoral work investigating thesynthesis of natural products, Andyjoined Beecham Pharmaceuticals asa medicinal chemist. He went on towork at Hoechst and subsequentlyAstraZeneca where he is SeniorDirector of Chemistry in theCancer and Infection department.Andy has worked in a variety oftherapeutic areas including infection,oncology, inflammation and CNS andhas particular interest in kinases astherapeutic targets.

Andy J Barker, Ph.D.Senior Director of ChemistryCancer and Infection Research AreaAstraZenecaCheshire, UK


Session II: Kinases II ■

57

David Rees joined Astex asDirector of Medicinal Chemis-

try in January 2003. Prior to Astex,he had 19 years experience as amedicinal chemist in the pharmaceu-tical industry, working with Parke-Davis, Organon and, most recently,AstraZeneca where he held theposition of Director and Head ofthe Medicinal Chemistry Departmentwith some 140 staff at the researchand development laboratories,Mölndal, Sweden. He has over 70publications and patents includingthe applications of peptidomimeticchemistry, combinatorial chemistryand supramolecular chemistry todrug discovery. He began hisresearch career as an organicchemist at Cambridge University,UK, where he obtained his PhD,

before moving to Prof. E. J. Corey’slaboratory at Harvard University

David Rees, Ph.D.Director of Medicinal ChemistryAstex TechnologyCambridge, UK



58

Alfonso de Dios, Ph.D.Research AdvisorDiscovery Chemistry Research and TechnologiesLilly Research LaboratioriesEli Lilly and CompanyIndianapolis, USA

Alfonso de Dios received hisdoctorate in organic chemistry

from Universidad Complutense deMadrid in 1994. He completed apostdoctoral fellowship at theUniversity of Michigan with JoeMarino working in asymmetricsynthesis of alkaloids and othernatural products. Back in Spain,Alfonso joined the faculty of theUniversidad Complutense for 2years as Associate Professor beforehe joined Lilly as a Senior OrganicChemist in 1998 working in theMedicinal Chemistry Division. In2003 he was promoted to PrincipalResearch Scientist and in 2005 toResearch Advisor.At Lilly,Alfonso deDios is recognized for his leadershipand technical contributions that haveimpacted different programs, espe-

cially within the kinase and oncologyplatform. In these assignments,Alfonsodesigned potent kinase inhibitors andefficient synthetic approaches fortheir accelerated development. Hehas forged strong cross functionalpartnerships with computational andanalytical chemists, biopharmaceuticsand ADME/Tox functional areas toaccelerate compounds from leadgeneration to the clinical candidateevaluation stages.Additionally,Alfonsode Dios has played a key role in thedevelopment of the Lilly R&D site inAlcobendas (Madrid) during the lastyears. His work, resulting in tenpatent applications, contributed toidentify promising 4 drug candidatesfor clinical studies.

Alfonso has recently accepted a3 year assignment to work at Lilly

Corporate Center in Indianapolis, asleader of a Medicinal Chemistryteam working on Oncology projects.



59

Zachary Knight graduated magnacum laude from the Depart-

ment of Chemistry at PrincetonUniversity in 1999. As an under-graduate he developed chemicalstrategies for mapping sites ofprotein phosphorylation. This workreceived the Grand Prize at the2002 Intercollegiate Inventor’sCompetition.

Zachary received his Ph. D. inChemistry and Chemical Biologyfrom UCSF in 2006. His doctoralresearch in the laboratory of KevanShokat focused on the synthesis ofisoform-specific inhibitors of PI3-kinase and the use of thesecompounds to dissect signaling byPI3-kinase isoforms. This workprovided the first structural rationalefor selective inhibition of a lipid

kinase and identified p110alpha asthe key PI3-kinase that controlsinsulin signaling. His graduate workwas supported by a fellowship fromthe Howard Hughes MedicalInstitute and recognized by the 2006UCSF Krevans DistinguishedDissertation Award.

Zachary will pursue postdoctoralresearch with Jeffrey Friedman atRockefeller University in 2007.

Zachary Knight, Ph.D.Postdoctoral fellowUniversity of Califórnia (UCSF)San Francisco, CA, USA


Martin Drysdale received hisB.Sc. (1986) and Ph.D. (1990)

in chemistry from St. AndrewsUniversity in Scotland. From the endof 1989 to 1991 he became a Parke-Davis Neuroscience Post-DoctoralResearch Fellow at the PD site inCambridge, UK and then spent 6years at Wellcome and Glaxo-Wellcome in the UK working onprojects in the CNS and inflam-matory therapeutic areas. In 1997he joined RiboTargets back inCambridge UK, then a Biotech start-up company, to head up and developthe chemistry group there workingon anti-infective targets. Aftersurviving several rounds of mergers,acquisitions and company namechanges he is now Director ofChemistry & Structural Science at

Vernalis working in the oncology andCNS areas, with a particular interestin Structure Based Drug Design andFragment Based Methods of hitidentification.

■ 2006 CNIO Cancer Conference: Inflammation and CancerSession IV: ATPases

60

Martin J. Drysdale, Ph.D.Director of Chemistry & Structural ScienceVernalis Ltd.Cambridge, UK


Session IV: ATPases ■

61

Paul Coleman received his B.A. inchemistry from the University of

Chicago in 1987. From there hepursued graduate studies at IndianaUniversity (Ph.D., organic chemistry)with Professor David R. Williamsfocusing his thesis work on the totalsyntheses of dollabelane andclavularane marine natural products.Paul then spent two years (1994-1996) in David A. Evans’ laboratoriesat Harvard University as a NationalInstitutes of Health PostdoctoralFellow. He and his colleaguescompleted the first synthesis of themarine cytotoxin, spongistatin 2.

In 1996, Paul joined MerckResearch Laboratories at a SeniorResearch Chemist in the departmentof Medicinal Chemistry, West Point,PA. Paul and his group developed a

series of potent, bioavailable avb3integrin antagonists that were eva-luated as bone resorption inhibitorsin human clinical trials. More recently,Paul and his colleagues havedeveloped small molecule kinesinspindle protein (KSP) inhibitors aspotential novel antitumor treatments.Co-crystallization of these inhibitorswith a KSP motor domain constructshowed that these compounds boundto the enzyme in a novel allostericlocation remote from the ATP-bindingsite.

Recent Publications:

Cox, C., et al. Kinesin spindleprotein (KSP) inhibitors. Struc-ture-based design of 5-alkyla-mino-3,5-diaryl-4,5-dihydropyra-

zoles as potent, water-solubleinhibitors of the mitotic kinesinKSP. Bioorganic & MedicinalChemistry Letters (2006), 16(12),3175-3179.

Fraley, M., et. al. Kinesin spindleprotein (KSP) inhibitors. Part 2:The design, synthesis, and cha-racterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of themitotic kinesin KSP. Bioorganic &Medicinal Chemistry Letters (2006),16(7), 1775-1779.

Coleman, P., et. al. Nonpeptide avb 3 Antagonists. Part 11: Dis-covery and Preclinical Evaluationof Potent a vb 3 Antagonists forthe Prevention and Treatment ofOsteoporosis. Journal of MedicinalChemistry (2004), 47(20), 4829-4837.

Paul J. Coleman, Ph.D.Senior Research Chemist Department of Medicinal ChemistryMerck Research LaboratoriesWest Point, USA


Graduate University of California, LosAngeles, CA.

1987-1992: Ph.D., Organic Chemistry• Graduate Research Advisor: Dr. Robert

W. Armstrong• Dissertation Title:

–Determination of the DNA bindingproperties of the antitumor antibioticCarzinophilin / Azinomycin B

Undergraduate Central Connecticut StateUniversity, New Britain, CT.1982-1987: B.S., Chemistry, Minor inBiology.• Research Director: Dr.Timothy D. Shine

–Synthesis of N,N-diacyl-ortho-anisidinesfor mechanistic studies of acyl migra-tion in ortho-phenols.

PROFESSIONAL EXPERIENCE2005-Current Bristol-Myers SquibbPharmaceutical Research Institute (BMS)• Associate Director, Cardiovascular

Chemistry

• Chemistry Discovery Working Group(DWG) leader:–HDL Elevation Program.

• Androgen Receptor Early DevelopmentTeam (EDT) member:–AR EDT Clinical and Commercial sub-team member

–Androgen Receptor DevelopmentManufacturing Team (DMT)

2004-2005 BMS• Associate Director, Oncology Chemistry• Chemistry DWG leader:

–AR antagonist program• Early phase Chemistry team leader:

–Early phase kinase programs• Team member: Exelixis Oncology

genomic targets collaboration–Chemistry liaison for IGBMCcollaboration:–Coordinate NHR collaboration

2000-2004 BMS• Group Leader, Oncology Chemistry

–Chemistry DWG leader:–AR antagonist and selective ARmodulator programs

–MEK antagonist program–Early phase Chemistry team leader:

–Apoptosis program collaborationwith Burnham Institute

–HDAC program

–PKCe program–17b-HSD-3 program

1998-2000 BMS• Senior Research Investigator II, Oncology

Chemistry• Chemistry DWG leader:

–AR Pan-antagonist program–Chemistry team member in cyclindependent kinase program

• Early phase Chemistry team leader:–17B-HSD-1 program–Telomerase program

1995-1998 American Home Products,Wyeth-Ayerst Research• Group Leader, Oncology Chemistry• Chemistry early phase team leader:

–Src kinase program–Mek kinase program–Bcl-2 apoptosis program–Tumor cell panel program

• Chemistry full phase team member:–VEGFR and EGFR kinase programs

1992-1995 American Cyanamid Company,Lederle Laboratories• Senior Research Scientist, Oncology

Chemistry• Chemistry early phase team leader:

–Tumor cell panel program• Chemistry full phase team member:

–Topoisomerase inhibitors program

■ 2006 CNIO Cancer Conference: Medicinal Chemistry in OncologySession V: Nuclear hormone receptors

62

Mark E. Salvati, Ph.D.Associate Director, Cardiovascular ResearchBristol-Myers Suibb CompanyPrinceton, NJ, USA



63

After graduating with B.A. (Hons.)and M.A. degrees from

Cambridge University in England, Dr.Bhatnagar continued his training withProf. Dr.T. Reichstein at the Universityof Basel, Switzerland, from where hereceived his PhD in Organic Che-mistry working on the isolation, struc-ture elucidation and synthesis of plantderived steroids. He subsequentlycompleted postdoctoral research inPhysiology at the Medical College ofVirginia in Richmond, Virginia wherehe worked on the characterization ofsteroid metabolizing enzymes.

Following 14 years as a Professorin the Departments of Obstetrics &Gynecology and Biochemistry at theMedical College of Virginia where hecarried out research into theendocrinology of pregnancy and the

reproductive endocrinology ofinfertility and taught endocrinology tomedical and graduate students, hejoined Ciba-Geigy in Basel. After 18years at Ciba-Geigy and Novartis,originally as a senior scientist, thenhead of the Endocrine Division wherehe lead the team which discoveredand developed the aromatase inhibitorletrozole (FemaraÆ), and subsequentlyin positions with progressively moreresponsibility in research planning anddevelopment and culminating with hisretirement from Novartis, Dr.Bhatnagar became President and CEOof World Wide Services Group, Ltd.,a consulting company to the pharma-ceutical industry. Dr. Bhatnagar alsoholds the position of Affiliate AssociateProfessor in the Department of Phy-siology at Virginia Commonwealth

University in Richmond, Virginia. Dr.Bhatnagar’s main research interestsare steroid endocrinology, develop-ment of aromatase inhibitors and thedevelopment of endocrine monitoringtechniques with applica-tions tohumans.

Dr. Bhatnagar is a member ofseveral professional societies includingthe Endocrine Society, the AmericanPhysiological Society, and the Societyfor the Study of Reproduction. Hehas been a member of a number ofeditorial boards of scientific periodicalsincluding Steroids and The Journal ofSteroid Biochemistry and MolecularBiology and has authored or coautho-red over 50 publications in peer-reviewed journals.

Ajay S. Bhatnagar, Ph.D.President and CEO of World Wide Services group, Ltd Affiliate Associate Professor in the Department of Physiologyat Virginia Commonwealth UniversityRichmond, VA, USA


Education:

She received her B.S. with Honorsin Chemistry 1975, Universidad

Complutense de Madrid (UCM);PhD. 1980, UCM; Postdoctoral stay(1981-1985) in the Sloan KetteringInstitute and Florida University(USA) (Fulbright Grant).

Academic Positions:1985-2004:Assistant Professor in theDepartment of Organic Chemistry(UCM University).2004 to present: Full Professor inthe Department of Organic Che-mistry (UCM University).

Research:Director of the Medicinal ChemistryGroup in the Department of OrganicChemistry (UCM University).

Research interest:– Design and development of new

serotoninergic agents: 5-HT1A and5-HT6 Rs.

– Development of new agents actingon the endogenous cannabinoidsystem: CB1, CB2Rs; monoacylgly-cerol lipase (MAGL).

– Design and synthesis of newanticancer drugs: Ras modulators,fatty acid synthase (FAS) andfibroblast growth factors (FGFs)inhibitors.

– Multidimensional approach to theidentification and characterizationof novel therapeutic targets anddevelopment of new drugs usingclick chemistry, quantum dots andproteomics.

Publications:110 original articles (Science, Mol.Pharmacol., Faseb J, Biochemistry, J. Med.Chem., J. Am. Chem. Soc ., J. Org.Chem…).

Patents:11 international patents (10 PCTand 1 USA).

Journals Editor:Associate Editor of Current Medi-cinal Chemistry-Central NervousSystem Agents.Regional Editor of Minireviews inCurrent Medicinal Chemistry.Editor Advisory Board of CurrentMedicinal Chemistry.


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María Luz López RodríguezProfessor in Organic ChemistryDirector of the Medicinal Chemistry GroupDepartment of Organic ChemistryUniversidad Complutense de Madrid (UCM University)Madrid, Spain



65

Prior to obtaining his Ph.D. in1998, Dr. Miller was awarded his

first patent, co-founded a smallbiotech company, out-licensed twotechnologies he had co-developed,was named ‘Inventor of the Year’ bythe University of Virginia, and helpedelucidate the complete andproblematic metabolism of a failingdrug (Felbatol®), including co-development of a related patienturinalysis and the out-licensing ofseveral “stabilized” Felbatol®analogues discovered and patentedwith co-inventors. During two yearsas a scientific officer at ColumbiaUniversity in the laboratories ofRonald Breslow, Dr. Millercoordinated and implementedlaboratory research in the generalareas of bioorganic and medicinal

chemistry. Key accomplishmentsduring this time include thedevelopment of novel inhibitors ofhistone deacetylase, later out-licensed to Aton Pharma, Inc. Dr.Miller also spent a year as amember of the Scientific AdvisoryBoard at UBS AG, where heprovided science and technologyadvising to the Global EquitiesDivision of one of Wall Street’slargest investment banks. In 2001, hejoined Aton Pharma, Inc., now awholly-owned subsidiary of Merck& Co., as Director of Chemistry andbegan directing the growth andproductivity of the company’sdiscovery & development chemistryprograms with a focus on growingthe company’s IP portfolio andsupporting the approval of

Zolinza™.As part of the corporatemanagement team, his mandate hasbeen to create and implement valueadding initiatives and strategies tomeet corporate goals. Keyaccomplishments in the areas ofdiscovery & development chemistryand intellectual property resulted insubstantive contributions to thecompany’s valuation that led to asuccessful transaction between AtonPharma and Merck and the approvalof Zolinza™. Dr. Miller hascontributed to more than 60publications, patents and patentapplication

Thomas A. Miller, Ph.D.Director of ChemistryDepartment of Drug Discovery and OptimizationMedicinal ChemistryMerck Research LabsBoston, MA, USA



66

Keith Menear received his PhDin 1986 from the University of

Leicester in natural productsynthesis. That same year he joinedCiba-GEIGY in the Advanced DrugDelivery Unit based in HorshamWest Sussex. In 1992 he moved toCiba Basel to work within thecardiovascular medicinal chemistrygroup on renin inhibitors. In 1994he returned to the Horsham site,now having merged with Sandoz toform Novartis, to eventually run thethrombosis research programme. In1997 he became Programme TeamLeader within the RespiratoryDisease therapeutic area principallyworking in the area of kinaseinhibition.

2001 saw a move to Chem-Ovation as Director of Chemistry,

a company which was acquired byKuDOS Pharmaceutical where thefocus of his work has been theexploitation of DNA repair targetsfor the treatment of cancer. At thebeginning of 2006 KuDOS wasacquired by AstraZeneca.

Keith Menear, Ph.D.Director of ChemistryKuDOS PharmaceuticalsCambridge Science Park, Cambridge, UK



67

Christopher Straub received hisBA in chemistry from Franklin

and Marshall College in 1990. Afterfive years as a synthetic chemist forE.I. DuPont de Nemours’ AgriculturalProducts division in Newark,Delaware, he returned to academicstudies under the direction ofProfessor Albert Padwa at EmoryUniversity in Atlanta, Georgia. Hecompleted his Ph.D. in 2000,developing and applying noveldipolarcycloaddition chemistry to thesynthesis of several small naturalproduct molecules. He continued hisstudies at the University of Texas atAustin, as an NIH PostdoctoralFellow under the direction ofStephen F. Martin. While at UTAustin his research was concernedwith using ring closing metathesis in

novel approaches to the macrocyclicnatural products Discodermalide andSarain A. In 2002 he joined NovartisPharmaceuticals in Summit, NJ andrelocated to Cambridge in 2004when the Novartis Institutes forBiomedical Research was established.His interests at Novartis have beenprimarily focused on seekinginhibitors to key components ofapoptosis suppressing pathways incancer cells, as well as seeking kinaseinhibitors.

Christopher S. Straub, Ph.D.Research Investigator IINovartis Institutes for Biomedical Research, Inc.Oncology ChemistryCambridge, Massachusetts, USA


Dr. Shaomen Wang received hisB.S. in Chemistry from Peking

University in 1986 and his Ph. D. inChemistry from Case WesternReserve University in 1992. Dr.Wangdid his postdoctoral training in drugdesign at the National CancerInstitute, NIH, between 1992-1996.Dr.Wang was Assistant Professor atGeorgetown University from 1996-2000 and Associate Professor from2000-2001. Dr. Wang joined thefaculty at the University of MichiganMedical School as a tenuredAssociate Professor in 2001 and waspromoted to Professor in 2006. Dr.Wang serves as the Co-Director ofthe Molecular Therapeutics Programat the University of MichiganComprehensive Cancer Center. Dr.Wang is the Principal Investigator of

a National Cooperative DrugDiscovery Group grant from theNational Cancer Institute, NIH, tothe University of Michigan andGeorgetown University.

Dr. Wang has published morethan 130 papers in peer-reviewedscientific journals and 80 meetingabstracts, and is an inventor onmore than 25 patents and patentapplications.

In addition to his academic role,Dr Wang is a co-founder of AscentaTherapeutics, which was establishedin 2003 and focuses on thedevelopment of molecularly targetedsmall-molecule anticancer drugs andserves on its Board of Directors.


68

Shaomen Wang, Ph.D.Professor Medicine, Pharmacology and Medicinal Chemistry Co-Director Molecular Therapeutics Program University of Michigan Comprehensive Cancer Center Ann Arbor, MI, USA



69

Dr. Haile Tecle is a ResearchFellow at Pfizer, Cambridge,

USA site. Haile had had multipleresponsibilities over the yearsincluding: project leader to the pan-erbB; MEK (CI-1014, PD 0325901);m1 muscarinic agonists (CI-1017);m1/m2 muscarinic agonists (CI-797);selective sigma ligands; dopamineautoreceptor agonists and dopamineantagonists projects. Haile obtainedhis Ph.D. degree in MedicinalChemistry from the University ofMichigan. His Ph.D. Thesis was onthe Design and Synthesis of PotentialChemoprophylactic Drugs againstSchistosomiasis.

Haile Tecle, Ph.D.Research FellowPfizer Research Technology CenterCambridge, MA, USA


Robert M. Borzilleri received aB.S. degree from Allegheny

College in Meadville, Pennsylvania in1989. He then obtained a Ph.D. fromThe Pennsylvania State University in1994, where he completed a totalsynthesis of the marine alkaloidpapuamine under the direction ofProfessor Steven Weinreb.As a NIHpostdoctoral research fellow in thelaboratory of Professor Dale Bogerat the Scripps Research Institute inLa Jolla, California, he initiated studiesdirected at the total synthesis ofglycopeptide antibiotic vancomycin.In 1997, he joined the DiscoveryChemistry Department at Bristol-Myers Squibb (BMS) in Princeton,New Jersey, where he has supportedseveral oncology programs. Notably,he discovered ixabepilone, the

lactam analogue of epothilone B thatis currently in Phase III clinical trialsfor metastatic breast cancer.Borzilleri was awarded the BMSOndetti & Cushman InnovationAward and BMS PRI President’sAward for his contributions to theepothilone program. He was achemistry project leader for the dualSrc/Abl inhibitor program, whichidentified dasatinib (Sprycel™) foradults with Philadelphia chromosomepositive leukemias that are resistantor intolerant to prior therapy. Hewas also a member of BMS’s anti-angiogenesis group, which identifiedseveral potent inhibitors of VEGFR-2, including the developmentcompound BMS-582664 (Phase II).Borzilleri is currently a GroupLeader in the Oncology Chemistry

Department working on theidentification of small moleculekinase inhibitors.

Selected Publications

Borzilleri, R.M. et al. 2000. J. Am.Chem. Soc. 122:8890-8897.Borzilleri, R.M.;Vite, G.D. 2002. DrugsFut. 27:1149-1163.Lombardo, L.J. et al. 2004. J. Med.Chem. 47:6658-6661.Borzilleri, R.M. et al. 2005. J. Med.Chem. 48:3991-4008.Bhide, R.S et al. 2006. J. Med. Chem.49:2143-2146.Borzilleri, R.M. et al. 2006. J. Med.Chem. 49:3766-3769.


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Robert M. Borzilleri, Ph.D.Group Leader, Oncology ChemistryBristol-Myers Squibb Pharmaceutical Research InstitutePrinceton, NJ, USA


List of Invited Speakers and Participants

CNIO_071_078_Listas 27/9/06 09:47 Página 71

Organisers and Invited Speakers

Fernando Albericio Science Park-UB

Barcelona, Spain [email protected]

Andy Barker AstraZeneca

Cheshire, UK [email protected]

Ajay S. Bhatnagar Novartis Pharma

Muttenz, Switzerland [email protected]

Robert M. Borzilleri Bristol-Myers Squibb

New Jersey, USA [email protected]

James Bischoff CNIO

Madrid, Spain [email protected]

Paul J. Coleman Merck Research Laboratories

West Point, USA [email protected]

Alfonso de Dios Lilly Research Laboratiories.

Indianapolis, USA [email protected]

Martin Drysdale Vernalis

Cambridge, UK [email protected]

Carlos Garcia-Echeverria Novartis Pharma

Basel, Switzerland [email protected]

Laurent Hennequin AstraZeneca

Reims, France [email protected]

Zachary Knight University of California

San Francisco, USA [email protected]

Lopez Rodriguez Maria Luz Universidad Complutense


David J. Matthews Exelixis Inc

San Francisco, USA [email protected]

List of Invited Speakers and Participants ■

73



74

Keith Menear KuDOS Pharmaceuticals


Thomas Miller Merck Research Laboratories

Boston, USA [email protected]

Andrew Mortlock AstraZeneca

Macclesfield, UK [email protected]

David Rees Astex Techology


Mark Salvati Bristol-Myers Squibb

Princeton, USA [email protected]

Tomi Sawyer Ariad Pharmaceuticals

Cambridge, USA [email protected]

Christopher Straub Novartis Institute for Biomedical Research

Massachusetts, USA [email protected]

Haile Tecle Pfizer Inc.

Cambridge, USA [email protected]

Shaomeng Wang University of Michigan

Ann Arbor, USA [email protected]


Participants

Bellinda Menhamú Salama Universidad Complutense

Madrid, Spain

Perla Breccia BioFocus DPI

Saffron Walden, UK [email protected]

Amancio Carnero CNIO


Luis Javier Cruz Ricondo Parc Cientific de Barcelona

Barcelona, España [email protected]

Leticia Cubo Universidad Autónoma de Madrid


Tommaso Cupido Parc Cientific de Barcelona


Jesus Angel de la Fuente Instituto Biomar, S.A.

Colmenar Viejo, Madrid, España [email protected]

Veronica Dodero Universidad de Santiago de Compostela

Santiago de Compostela, Spain [email protected]

Antonio Fernández Instituto Biomar, S.A.

León, España [email protected]

Joan-Carles Fernàndez Parc científic de Barcelona


Rosario González-Muñiz Instituto de Química Médica


Fulvio Gualtieri University of Florence

Florence, Italy [email protected]

Rosario Herranz Instituto de Química Médica (CSIC)



75


Jose Jaen-Oltra Cognitalis

Valencia, Spain [email protected]

Olaf Kinzel IRBM, MRL Rome

Rome, Italy [email protected]

Fernando López-Ríos Hospital Universitario “12 de Octubre”


Fabrizio Manetti Università degli Studi di Siena

Siena, Italy [email protected]

José Luis Marco-Contelles Instituto de Química Orgánica General (CSIC)


Sonsoles Martin Santamaría Universidad San Pablo CEU

Boadilla del Monte, Madrid, Spain [email protected]

Mariano Martínez-Vázquez Universidad Nacional Autónoma de México

México, D. F., México [email protected]

Laurence Mevellec Johnson

Val de Reuil Cedex, France [email protected]

Saverio Minucci Congenia Srl

Milan, Italy [email protected]

María Teresa Molina Instituto de Química Médica (CSIC)


John Munroe Lilly

Indianapolis, USA [email protected]

Chris Northfield Vernalis


M.ª Concepción Pérez Melero University of Salamanca

Salamanca, Spain [email protected]

Cecilia Portela Pallares Universidade de Santiago de Compostela

Santiago de Compostela, Spain [email protected]


76


Sonsoles Rodriguez Northerm Institute for Cancer Research, Newcastle University

Newcastle upon Tyne, UK [email protected]

Ana Rodríguez López CNIO


Concepcion Sanchez-Martinez Lilly Spain

Alcobendas, Madrid, Spain [email protected]

Claudi Sola Merck Farma y Quimica S.A.

Mollet del Vallés, Spain [email protected]

Connie Sun Poniard Pharmaceuticals, Inc.

South San Francisco, USA [email protected]

Timothy Thomson IBMB-CSIC


Kristof Van Emelen Johnson

2340 Beerse, Belgium [email protected]

Mario Varasi DAC Srl

Milan, Italy [email protected]

Stephan Zahn Boehringer Ingelheim Austria GmbH

Vienna,Austria [email protected]


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Acknowledgements

CNIO_095_098_Acknowlmts 20/9/06 09:05 Página 95


As a non-profit organisation, we would like to thank our CNIO Cancer Conferences (CCC’s) collaborators.Such contribution helps to ensure that our conferences will continue to establish the CNIO as a point ofreference for the international cancer research community.

For information about collaboration opportunities, please contact us ([email protected])

Acknowledgements ■

97



Notes

CNIO_099_104_Notes 20/9/06 09:05 Página 99



Notes ■




Notes ■




Previous CNIO Cancer Conferences

CNIO_105_108_Previous 20/9/06 09:06 Página 105


Previous CNIO Cancer Conferences ■

107

PREVIOUS CNIO CANCER CONFERENCES

2003TARGETED SEARCH FOR ANTICANCER DRUGS

ORGANISERS:AMANCIO CARNERO (CNIO, MADRID, SPAIN), DAVID BEACH (WOLFSON INSTITUTE FOR

BIOMEDICAL RESEARCH, LONDON, UK)DATES: MARCH, 17-19, 2003

SMALL GTPASES IN HUMAN CARCINOGENESIS

ORGANISERS: JUAN CARLOS LACAL (INSTITUTO DE INVESTIGACIONES BIOMÉDICAS, MADRID, SPAIN), CHANNING

J. DER (UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL, USA), SHUH NARUMIYA (KYOTO UNIVERSITY, JAPAN)DATES: JUNE, 16-18, 2003

APOPTOSIS AND CANCER

ORGANISERS: GABRIEL NUÑEZ (UNIVERSITY OF MICHIGAN,ANN ARBOR, USA), MARISOL SOENGAS (UNIVERSITY

OF MICHIGAN,ANN ARBOR, USA) AND SCOTT LOWE (COLD SPRING HARBOR LABORATORY, COLD SPRING

HARBOR, USA)DATES: DECEMBER, 1-3, 2003

2004STRUCTURAL BIOLOGY OF CANCER TARGETS

ORGANISERS: ERNEST LAUE (UNIV. OF CAMBRIDGE,CAMBRIDGE, UK), GUILLERMO MONTOYA (CNIO, MADRID,SPAIN), ALFRED WITTINHOFER (MAX PLANK INSTITUTE, DORTMUND, GERMANY)DATES: SEPTEMBER 27-29, 2004

CADHERINS, CATENINS AND CANCER

ORGANISERS:AMPARO CANO (IIB-CSIC, MADRID, SPAIN), HANS CLEVERS (NETHERLANDS INSTITUTE FOR

DEVELOPMENTAL BIOLOGY, UTRECHT,THE NETHERLANDS), JOSÉ PALACIOS (CNIO, MADRID, SPAIN),FRANS VAN ROY (GHENT UNIVERSITY, GHENT, BELGIUM)DATES: NOVEMBER 29-DECEMBER 1, 2004


2005ANIMAL TUMOUR MODELS AND FUNCTIONAL GENOMICS

ORGANISERS:ALLAN BALMAIN (UCSF COMPREHENSIVE CANCER CENTER, SAN FRANCISCO, USA), MARIANO

BARBACID (CNIO, MADRID, SPAIN),ANTON BERNS (THE NETHERLANDS CANCER INSTITUTE,AMSTERDAM,THE

NETHERLANDS),TYLER JACKS (CENTER FOR CANCER RESEARCH, MIT, CAMBRIDGE, USA)DATES: MARCH 7-9, 2005

MAP KINASES AND CANCER

ORGANISERS: PHILIP COHEN (UNIVERSITY OF DUNDEE, DUNDEE, UK), ROGER DAVIS (UNIVERSITY OF

MASSACHUSETTS MEDICAL SCHOOL,WORCESTER, USA), CHRIS MARSHALL (INSTITUTE OF CANCER RESEARCH,LONDON, UK),ANGEL NEBREDA (CNIO, MADRID, SPAIN)DATES: MAY 30 - JUNE 1, 2005

CANCER AND AGING

ORGANISERS: MARÍA BLASCO, CNIO, MADRID, SPAIN; KATHLEEN COLLINS, UCB, BERKELEY, USA,JAN HOEIJMAKERS, ERASMUS UNIVERSITY, ROTTERDAM,THE NETHERLANDS, MANUEL SERRANO, CNIO,MADRID, SPAIN

DATES: NOVEMBER 7-9, 2005

2006PTEN AND THE AKT ROUTE

ORGANISERS:ANA CARRERA (CENTRO NACIONAL DE BIOTECNOLOGÍA, CSIC, MADRID, SPAIN),PIER PAOLO PANDOLFI (MEMORIAL SLOAN-KETTERING CANCER CENTER, NEW YORK, USA),PETER VOGT (SCRIPPS RESEARCH INSTITUTE, LA JOLLA, USA)DATES: MAY 8-10, 2006

INFLAMMATION AND CANCER

ORGANISERS: CURT HARRIS (NATIONAL CANCER INSTITUTE, BETHESDA, MD, USA), RAY DUBOIS (VANDERBLIT

UNIVERSITY MEDICAL CENTER, USA) JORGE MOSCAT (CENTER OF MOLECULAR BIOLOGY "SEVERO OCHOA",MADRID, SPAIN), MANUEL SERRANO (CNIO, MADRID, SPAIN)DATES: MAY 22-24, 2006

108


Forthcoming CNIO Events

CNIO_109_112_Forthcoming 20/9/06 09:06 Página 109


Forthcoming CNIO Events ■

111

FORTHCOMING CNIO CANCER CONFERENCES(Detailed information will be published at www.cnio.es/ccc)

2006TELOMERES AND TELOMERASE

CNIO / JOSEF STEINER CANCER CONFERENCE

ORGANISERS: MARIA BLASCO, CNIO, MADRID, SPAIN; JERRY SHAY, UT SOUTHWESTERN MEDICAL CENTER,DALLAS, USADATES: NOVEMBER 13-15, 2006

2007MOLECULAR MECHANISMS IN LYMPHOID NEOPLASM

ORGANISERS: ELIAS CAMPO, HOSPITAL CLINIC, BARCELONA, RICCARDO DALLA FAVERA, COLUMBIA UNIVERSITY, NEW

YORK, USA; ELAINE JAFFE, NCI, BETHESDA, USA; MIGUEL ÁNGEL PIRIS, CNIO, MADRID, SPAIN

DATES: FEBRUARY 19-21, 2007

MYC AND THE TRANSCRIPTIONAL CONTROL OF PROLIFERATION AND ONCOGENESIS

ORGANISERS: ROBERT N. EISENMAN, FRED HUTCHINSON CANCER RESEARCH CENTER, SEATTLE, USA; MARTIN

EILERS, UNIVERSITY OF MARBURG, MARBURG, GERMANY; JAVIER LEÓN, UNIVERSIDAD DE CANTABRIA, SANTANDER,SPAIN

DATES: JUNE 11-13, 2007

LINKS BETWEEN CANCER, REPLICATION STRESS AND GENOMIC INTEGRITY. NOVEMBER 5-7ORGANISERS: OSCAR FERNÁNDEZ-CAPETILLO, CNIO, MADRID, SPAIN; JIRI LUKAS, DANISH CANCER SOCIETY,COPENHAGEN, DENMARK; JUAN MÉNDEZ, CNIO, MADRID, SPAIN;ANDRE NUSSENZWEIG, NCI/NIH, BETHESDA, USADATES: NOVEMBER 5-7, 2007


112

OTHER FORTHCOMING CNIO EVENTS(Detailed information will be published at www.cnio.es/meetings and www.cnio.es/symposium)

2006MEETING ON BLADDER CANCER: SEARCHING TARGETS AND BIOMARKERS USING GENOMIC AND PROTEOMIC APPROACHES

ORGANISERS: MARTA SÁNCHEZ-CARBAYO (CNIO, MADRID); CARLOS CORDÓN CARDO (MSKCC, NEW YORK)DATES: OCTOBER 5-6, 2006

SYMPOSIUM ON MOLECULAR MARKERS IN CANCER THERAPHY

ORGANISERS: MIGUEL A. PIRIS (CNIO, MADRID), MONTSERRAT SÁNCHEZ-CÉSPEDES (CNIO, MADRID)DATES: NOVEMBER 27-29, 2006

MEETING ON SNPS ANALYSIS, TOOLS AND APPLICATIONS

ORGANISERS: M. ROBLEDO (CNIO, MADRID), X.DOPAZO (IPF,VALENCIA). J. BENITEZ (CNIO, MADRID)DATES: DECEMBER 1-2, 2006

2007SYMPOSIUM ON ONCOGENES AND HUMAN CANCER: THE NEXT 25 YEARS

ORGANISERS: M. BARBACID (CNIO, MADRID)AND NATURE PUBLISHING GROUP

DATES: OCTOBER 3-6 2007


Medicinal Chemistry in Oncology - CNIO91_booklet.pdfNotes Previous CNIO Cancer Conferences ... 2006 CNIO Cancer Conference: Medicinal Chemistry in Oncology CNIO_005_010_Programmes

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