Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582)

…, LM Castriotta, D Cook, M Hattersley…

文献索引：Hennessy, Edward J.; Adam, Ammar; Aquila, Brian M.; Castriotta, Lillian M.; Cook, Donald; Hattersley, Maureen; Hird, Alexander W.; Huntington, Christopher; Kamhi, Victor M.; Laing, Naomi M.; Li, Danyang; MacIntyre, Terry; Omer, Charles A.; Oza, Vibha; Patterson, Troy; Repik, Galina; Rooney, Michael T.; Saeh, Jamal C.; Sha, Li; Vasbinder, Melissa M.; Wang, Haiyun; Whitston, David Journal of Medicinal Chemistry, 2013 , vol. 56, # 24 p. 9897 - 9919

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被引用次数: 17

摘要

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50= 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation ...