| Literature DB >> 22413863 |
John A Flygare1, Maureen Beresini, Nageshwar Budha, Helen Chan, Iris T Chan, Sravanthi Cheeti, Frederick Cohen, Kurt Deshayes, Karl Doerner, S Gail Eckhardt, Linda O Elliott, Bainian Feng, Matthew C Franklin, Stacy Frankovitz Reisner, Lewis Gazzard, Jason Halladay, Sarah G Hymowitz, Hank La, Patricia LoRusso, Brigitte Maurer, Lesley Murray, Emile Plise, Clifford Quan, Jean-Philippe Stephan, Shin G Young, Jeffrey Tom, Vickie Tsui, Joanne Um, Eugene Varfolomeev, Domagoj Vucic, Andrew J Wagner, Heidi J A Wallweber, Lan Wang, Joseph Ware, Zhaoyang Wen, Harvey Wong, Jonathan M Wong, Melisa Wong, Susan Wong, Ron Yu, Kerry Zobel, Wayne J Fairbrother.
Abstract
A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.Entities:
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Year: 2012 PMID： 22413863 PMCID： PMC3366583 DOI： 10.1021/jm300060k
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446