Design, synthesis and evaluation of inhibitor of apoptosis protein (IAP) antagonists that are highly selective for the BIR2 domain of XIAP

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• 作者：Robert J. Ardecky ; Kate Welsh ; Darren Finlay ; Pooi San Lee ; Marcos Gonz¨¢lez-L¨®pez ; Santhi Reddy Ganji ; Palaniy ; i Ravanan ; Peter D. Mace ; Stefan J. Riedl ; Kristiina Vuori ; John C. Reed ; Nicholas D.P. Cosford
• 关键词：Apoptosis ; XIAP ; Monovalent Smac mimetics ; Probe compounds
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：23
• 期：14
• 页码：4253-4257
• 全文大小：934 K

文摘

We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist g class=""boldFont"">8qg> (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP.