title: Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold.
abstract: 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.
authors.affiliation: Departments of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. fcohen@gene.com
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Linda O
authors.initials: LO
authors.lastname: Elliott
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goncharov
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Keteltas
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Franklin
authors.forename: Stacy
authors.initials: S
authors.lastname: Frankovitz
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
mesh_terms: 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
chemical_list: D053961:Azabicyclo Compounds; D051034:Inhibitor of Apoptosis Proteins; D009795:Octanes