Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies
- Author(s)
- Condon, SM; Mitsuuchi, Y; Deng, Y; Laporte, MG; Rippin, SR; Haimowitz, T; Alexander, MD; Kumar, PT; Hendi, MS; Lee, YH; Benetatos, CA; Yu, G; Kapoor, GS; Neiman, E; Seipel, ME; Burns, JM; Graham, MA; McKinlay, MA; Li, X; Wang, J; Shi, Y; Feltham, R; Bettjeman, B; Cumming, MH; Vince, JE; Khan, N; Silke, J; Day, CL; Chunduru, SK;
- Details
- Publication Year 2014-05-08,Volume 57,Issue #9,Page 3666-77
- Journal Title
- Journal of medicinal chemistry
- Publication Type
- Journal Article
- 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-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.
- Publisher
- ACS
- Research Division(s)
- Cell Signalling And Cell Death; Inflammation
- Publisher's Version
- https://doi.org/10.1021/jm500176w
- Terms of Use/Rights Notice
- Copyright © 2014 American Chemical Society
Creation Date: 2014-05-12 04:46:52