Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)

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• 作者：John A. Flygare ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4101-4113
• 全文大小：566K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

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 卤 3 mL/min/kg, and the volume of distribution was 0.6 卤 0.2 L/kg.