1. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)
- Author
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Andrew J. Wagner, Ron Yu, Sarah G. Hymowitz, S. Gail Eckhardt, Joanne Um, Shin G. Young, Bainian Feng, Maureen Beresini, Iris T. Chan, John A. Flygare, Domagoj Vucic, Jason Halladay, Jeffrey Tom, Linda O. Elliott, Karl Doerner, Sravanthi Cheeti, Heidi J.A. Wallweber, Lan Wang, Emile Plise, Lesley J. Murray, Vickie Tsui, Clifford Quan, Eugene Varfolomeev, Melisa L. Wong, Hank La, Frederick Cohen, Patricia LoRusso, Nageshwar Budha, Jonathan M. Wong, Jean Philippe Stephan, Kerry Zobel, Helen Chan, Joseph A. Ware, Lewis J. Gazzard, Matthew C. Franklin, Brigitte Maurer, Kurt Deshayes, Harvey Wong, Zhaoyang Wen, Wayne J. Fairbrother, Stacy Frankovitz Reisner, and Susan Wong
- Subjects
Male ,Apoptosis Inhibitor ,Cell Survival ,Ubiquitin-Protein Ligases ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Pharmacology ,Inhibitor of apoptosis ,Binding, Competitive ,Article ,Inhibitor of Apoptosis Proteins ,Pharmacokinetics ,Cell Line, Tumor ,Drug Discovery ,Thiadiazoles ,medicine ,Baculoviral IAP Repeat-Containing 3 Protein ,Animals ,Humans ,Clinical Trials, Phase I as Topic ,Chemistry ,Antagonist ,Cancer ,medicine.disease ,XIAP ,Caspases ,Molecular Medicine ,Female - 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.
- Published
- 2012