Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain

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• 作者：Andrew F. Donnell ; Christophe Michoud ; Kenneth C. Rupert ; Xiaochun Han ; Douglas Aguilar ; Karl B. Frank ; Adrian J. Fretland ; Lin Gao ; Barry Goggin ; J. Heather Hogg ; Kyoungja Hong ; Cheryl A. Janson ; Robert F. Kester ; Norman Kong ; Kang Le ; Shirley Li ; Weiling Liang ; Louis J. Lombardo ; Yan Lou ; Christine M. Lukacs ; Steven Mischke ; John A. Moliterni ; Ann Polonskaia ; Andrew D. Schutt ; Dave S. Solis ; Anthony Specian ; Robert T. Taylor ; Martin Weisel ; Stacy W. Remiszewski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：7772-7787
• 全文大小：661K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.