Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies
Publication Year 2014-05-08, Volume 57, Issue #9, Page 3666-77
Journal Title
Journal of medicinal chemistry
Publication Type
Journal Article
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-kappaB 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.
WEHI Research Division(s)
Cell Signalling And Cell Death; Inflammation
Publisher's Version
Rights Notice
Copyright © 2014 American Chemical Society

Creation Date: 2014-05-12 04:46:52
Last Modified: 0001-01-01 12:00:00
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