Journal article
Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies
SM Condon, Y Mitsuuchi, Y Deng, MG Laporte, SR Rippin, T Haimowitz, MD Alexander, PT Kumar, MS Hendi, YH Lee, CA Benetatos, G Yu, GS Kapoor, E Neiman, ME Seipel, JM Burns, MA Graham, MA McKinlay, X Li, J Wang Show all
Journal of Medicinal Chemistry | Published : 2014
DOI: 10.1021/jm500176w
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 knoc..
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Awarded by NHMRC
Funding Acknowledgements
The authors acknowledge the support from our colleagues at TetraLogic Pharmaceuticals (Malvern, PA) and our co-workers at the START Preclinical Research Group (San Antonio, TX) and the Piedmont Research Center, LLC (Morrisville, NC) for conducting the animal experiments described in this paper. J.S. was supported by NHMRC grants (Grants 433013, 541902, 461221, 1046986) and fellowships (Grant 541901). C.L.D. acknowledges financial support from the Health Research Council of New Zealand. We thank C. Glenn Begley for critical reading of this manuscript.