title: Design, synthesis and evaluation of inhibitor of apoptosis protein (IAP) antagonists that are highly selective for the BIR2 domain of XIAP.
abstract: We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist 8q (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP.
authors.affiliation: Program in Apoptosis and Cell Death, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Darren
authors.initials: D
authors.lastname: Finlay
authors.forename: Pooi San
authors.initials: PS
authors.lastname: Lee
authors.forename: Marcos
authors.initials: M
authors.lastname: González-López
authors.forename: Santhi Reddy
authors.initials: SR
authors.lastname: Ganji
authors.forename: Palaniyandi
authors.initials: P
authors.lastname: Ravanan
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Riedl
authors.forename: Kristiina
authors.initials: K
authors.lastname: Vuori
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C585744:ML183 peptide; D009842:Oligopeptides; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein