Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain

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• 作者：Robert F. Kester ; Andrew F. Donnell ; Yan Lou ; Stacy W. Remiszewski ; Louis J. Lombardo ; Shaoqing Chen ; Nam T. Le ; Jennifer Lo ; John A. Moliterni ; Xiaochun Han ; J. Heather Hogg ; Weiling Liang ; Christophe Michoud ; Kenneth C. Rupert ; Steven Mischke ; Kang Le ; Martin Weisel ; Cheryl A. Janson ; Christine M. Lukacs ; Adrian J. Fretland ; Kyoungja Hong ; Ann Polonskaia ; Lin Gao ; Shirley Li ; Dave S. Solis ; Doug Aguilar ; Christine Tardell ; Mark Dvorozniak ; Shahid Tannu ; Edmund C. Lee ; Andy D. Schutt ; Barry Goggin
• 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：7788-7803
• 全文大小：771K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNF伪, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC₅₀ = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNF伪 in vitro.