Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold.
A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.
Cohen
Frederick
F
Departments of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. fcohen@gene.com
Alicke
Bruno
B
Elliott
Linda O
LO
Flygare
John A
JA
Goncharov
Tatiana
T
Keteltas
Stephen F
SF
Franklin
Matthew C
MC
Frankovitz
Stacy
S
Stephan
Jean-Philippe
JP
Tsui
Vickie
V
Vucic
Domagoj
D
Wong
Harvey
H
Fairbrother
Wayne J
WJ
D000284:Administration, Oral; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009795:Octanes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D053961:Azabicyclo Compounds; D051034:Inhibitor of Apoptosis Proteins; D009795:Octanes