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

被引：128

作者：

Condon, Stephen M. ^{[1
]}

Mitsuuchi, Yasuhiro ^{[1
]}

Deng, Yijun ^{[1
]}

LaPorte, Matthew G. ^{[1
]}

Rippin, Susan R. ^{[1
]}

Haimowitz, Thomas ^{[1
]}

Alexander, Matthew D. ^{[1
]}

Kumar, Pavan Tirunahari ^{[1
]}

Hendi, Mukta S. ^{[1
]}

Lee, Yu-Hua ^{[1
]}

Benetatos, Christopher A. ^{[1
]}

Yu, Guangyao ^{[1
]}

Kapoor, Gurpreet Singh ^{[1
]}

Neiman, Eric ^{[1
]}

Seipel, Martin E. ^{[1
]}

Burns, Jennifer M. ^{[1
]}

Graham, Martin A. ^{[1
]}

McKinlay, Mark A. ^{[1
]}

Li, Xiaochun ^{[2
]}

Wang, Jiawei ^{[2
]}

Shi, Yigong ^{[2
]}

Feltham, Rebecca ^{[3
]}

Bettjeman, Bodhi ^{[4
]}

Cumming, Mathew H. ^{[4
]}

Vince, James E. ^{[5
,6
]}

Khan, Nufail ^{[5
,6
]}

Silke, John ^{[3
,5
,6
]}

Day, Catherine L. ^{[4
]}

Chunduru, Srinivas K. ^{[1
]}

机构：

[1] TetraLog Pharmaceut Inc, Malvern, PA 19355 USA

[2] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China

[3] La Trobe Univ, Dept Biochem, Bundoora, Vic 3086, Australia

[4] Univ Otago, Dept Biochem, Dunedin 9054, New Zealand

[5] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[6] Univ Melbourne, Dept Med Biol, Parkville, Vic 3050, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 09期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

X-LINKED INHIBITOR; NF-KAPPA-B; APOPTOSIS PROTEINS IAPS; ANTAGONISTS INDUCE; STRUCTURAL BASIS; BIR3; DOMAIN; XIAP; ACTIVATION; BINDING; CIAP1;

D O I：

10.1021/jm500176w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-kappa 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 P-2' position of 1 was critical to this differential activity, and this improved tolerability has allowed 1 to proceed into clinical studies.

引用

页码：3666 / 3677

页数：12

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