Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

详细信息    查看全文

• 作者：Jean-Marc Lapierre ; Sudharshan Eathiraj ; David Vensel ; Yanbin Liu ; Cathy O. Bull ; Susan Cornell-Kennon ; Shin Iimura ; Eugene W. Kelleher ; Darin E. Kizer ; Steffi Koerner ; Sapna Makhija ; Akihisa Matsuda ; Magdi Moussa ; Nivedita Namdev ; Ronald E. Savage ; Jeff Szwaya ; Erika Volckova ; Neil Westlund ; Hui Wu ; Brian Schwartz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6455-6469
• 全文大小：575K
• 年卷期：0
• ISSN：1520-4804

文摘

The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.