Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies.

Journal: Journal Of Medicinal Chemistry
Published:
Abstract

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

Authors
Stephen Condon, Yasuhiro Mitsuuchi, Yijun Deng, Matthew Laporte, Susan Rippin, Thomas Haimowitz, Matthew Alexander, Pavan Kumar, Mukta Hendi, Yu-hua Lee, Christopher Benetatos, Guangyao Yu, Gurpreet Kapoor, Eric Neiman, Martin Seipel, Jennifer Burns, Martin Graham, Mark Mckinlay, Xiaochun Li, Jiawei Wang, Yigong Shi, Rebecca Feltham, Bodhi Bettjeman, Mathew Cumming, James Vince, Nufail Khan, John Silke, Catherine Day, Srinivas Chunduru