Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases

  • J Med Chem. 2008 Dec 25;51(24):8158-62. doi: 10.1021/jm801254r.
Yuefeng Peng  1 ,  Haiying Sun ,  Zaneta Nikolovska-Coleska ,  Su Qiu ,  Chao-Yie Yang ,  Jianfeng Lu ,  Qian Cai ,  Han Yi ,  Sanmao Kang ,  Dajun Yang ,  Shaomeng Wang
Affiliations
  • 1. Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
PMID: 19049347 DOI: 10.1021/jm801254r
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.