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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of
Yuefeng Peng1, Haiying Sun, Zaneta Nikolovska-Coleska
1Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Abstract:
A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.
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