Current Literature Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation ACS Med. Chem. Lett. 2017, 139, 6046. Evan Carder Wipf Group Current Literature November 18, 2017 11/18/17 1 Evan Carder @ Wipf Group N N S O O O HN O NH O O O N H F F Cl O N N N HN O N H Proteasomal degradation BCR-ABL BCR-ABL Ub Ub Ub Ub BCR-ABL E3 Ligase E2 Ub Ub
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Current Literature!!Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation!
!ACS Med. Chem. Lett. 2017, 139, 6046. !
Evan Carder!Wipf Group Current Literature!
November 18, 2017
11/18/17 1EvanCarder@WipfGroup
NNS
O
O O HN O
NHO
OO NHFF
Cl
O
NN
NHNO
NH
Proteasomal degradation
BCR-ABL BCR-ABL
UbUb
Ub
Ub
BCR-ABL
E3 Ligase
E2
Ub
Ub
11/18/17! 2EvanCarder@WipfGroup
Normal !chromosomal 9!
Normal !chromosomal 22!
break! translocation!
Transformed!chromosomal 9!
Transformed!chromosomal 22!
ABL!
BCR!
JCI 2007, 117, 2036.!Nat. Rev. Cancer 2007, 7, 345. !
Structurally similar to endogenous ligand!Employ rational drug design!Varying degrees of specificity!Highly susceptible to drug resistance !
!§ Nonothosteric/Allosteric Modulators!
Lack an endogenous ligand!Unique chemical structures!Elevated target selectivity!Reduced off-targets !Spatio-temporal specificity!Reduced susceptibility to drug resistance !
Nonorthosteric site
Orthosteric site
POI
Hypothesis – Application of an allosteric BCR-ABL PROTAC induces BCR-ABL protein degradation !
11/18/17! 8EvanCarder@WipfGroup
PROTAC AllostericABL Ligand
E3 LigaseLigand
ABL
E3 Ligase
E2
Ub
Ub
BCR-ABL protein degradation!Development of an allosteric BCR-ABL PROTAC!
Phase I! Phase II!
ABL Allosteric-site Inhibitors!
11/18/17! 9EvanCarder@WipfGroup
Nature 2010, 463, 28.!Nature 2017, 543, 733. !
PDB: 5MO4
ABL
OFF
ClHN N N
HN N
OH
ABL001
OFF
FHN
N N O
NH2
GNF-2
ABL !Kinase
ATP-binding !site
Myristate!binding site
Target Myristate-binding site
E3-Ubiquitin Ligands!
11/18/17! 10EvanCarder@WipfGroup
Nat. Drug. Disc. 2017, 16, 101.!
N
NO
ONHN
O
Nutlin-3aMDM2 Ligand
O
Cl
Cl
HO
ONH
O
OH
NH2
BestatincIAP Ligand
N
NH2
O
ONH
O
O
PomalidomideCRBN Ligand
N
OHO
HOO
HN
SN
VHL Ligand
IAPs!!MDM2!!Von Hippel-Lindau!!Cereblon!
!!
E3-Ubiquitin Ligase!E3 Ligase
OO
SN
N
ONH
OHN
4cIAP Ligand
Design of PROTAC!
11/18/17! 11EvanCarder@WipfGroup
PROTAC AllostericABL Ligand
E3 LigaseLigand
Linker
OOO
Ethylene glycol linkerOFF
ClHN N N
HN N
OH
ABL001 OO
SN
N
ONH
OHN
4cIAP Ligand
Structural Analysis of ABL001 bound ABL Kinase!
11/18/17! 12EvanCarder@WipfGroup
Nature 2017, 543, 733. !
PDB: 5MO4
Positioning of the linker
solvent !exposed region
Surface view of ABL Kinase
ABL
OFF
ClHN N N
HN N
OH
ABL001
OO
SN
N
ONH
OHN
4cIAP Ligand
Structural Analysis of IAP Ligand !
11/18/17! 13EvanCarder@WipfGroup
J. Biological Chemistry 2017, 292, 4556.!J. Med. Chem. Article ASAP!Bioorg. & Medi.Chem. Lett. 2010, 20, 2229.!