Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies

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• 作者：Stephen M. Condon ; Yasuhiro Mitsuuchi ; Yijun Deng ; Matthew G. LaPorte ; Susan R. Rippin ; Thomas Haimowitz ; Matthew D. Alexander ; Pavan Tirunahari Kumar ; Mukta S. Hendi ; Yu-Hua Lee ; Christopher A. Benetatos ; Guangyao Yu ; Gurpreet Singh Kapoor ; Eric Neiman ; Martin E. Seipel ; Jennifer M. Burns ; Martin A. Graham ; Mark A. McKinlay ; Xiaochun Li ; Jiawei Wang ; Yigong Shi ; Rebecca Feltham ; Bodhi Bettjeman ; Mathew H. Cumming ; James E. Vince ; Nufail Khan ; John Silke ; Catherine L. Day ; Srinivas K. Chunduru
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 8, 2014
• 年：2014
• 卷：57
• 期：9
• 页码：3666-3677
• 全文大小：528K
• 年卷期：v.57,no.9(May 8, 2014)
• ISSN：1520-4804

文摘

Birinapant (1) is a second-generation bivalent antagonist of IAP proteins that is currently undergoing clinical development for the treatment of cancer. Using a range of assays that evaluated cIAP1 stability and oligomeric state, we demonstrated that 1 stabilized the cIAP1-BUCR (BIR3-UBA-CARD-RING) dimer and promoted autoubiquitylation of cIAP1 in vitro. Smac-mimetic 1-induced loss of cIAPs correlated with inhibition of TNF-mediated NF-魏B activation, caspase activation, and tumor cell killing. Many first-generation Smac-mimetics such as compound A (2) were poorly tolerated. Notably, animals that lack functional cIAP1, cIAP2, and XIAP are not viable, and 2 mimicked features of triple IAP knockout cells in vitro. The improved tolerability of 1 was associated with (i) decreased potency against cIAP2 and affinity for XIAP BIR3 and (ii) decreased ability to inhibit XIAP-dependent signaling pathways. The P₂鈥?position of 1 was critical to this differential activity, and this improved tolerability has allowed 1 to proceed into clinical studies.