|
|||||
|
|
Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152) |
|
| Authors: | Flygare John A Beresini Maureen Budha Nageshwar Chan Helen Chan Iris T Cheeti Sravanthi Cohen Frederick Deshayes Kurt Doerner Karl Eckhardt S Gail Elliott Linda O Feng Bainian Franklin Matthew C Reisner Stacy Frankovitz Gazzard Lewis Halladay Jason Hymowitz Sarah G La Hank LoRusso Patricia Maurer Brigitte Murray Lesley Plise Emile Quan Clifford Stephan Jean-Philippe Young Shin G Tom Jeffrey Tsui Vickie Um Joanne Varfolomeev Eugene Vucic Domagoj Wagner Andrew J Wallweber Heidi J A Wang Lan Ware Joseph Wen Zhaoyang Wong Harvey Wong Jonathan M Wong Melisa Wong Susan Yu Ron Zobel Kerry |
| Affiliation: | Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. jflygare@gene.com |
| 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. |
| Keywords: | |
| 本文献已被 PubMed 等数据库收录！ | |