Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins

  • J Med Chem. 2006 Oct 19;49(21):6139-42. doi: 10.1021/jm060460o.
Guoping Wang  1 ,  Zaneta Nikolovska-Coleska ,  Chao-Yie Yang ,  Renxiao Wang ,  Guozhi Tang ,  Jie Guo ,  Sanjeev Shangary ,  Su Qiu ,  Wei Gao ,  Dajun Yang ,  Jennifer Meagher ,  Jeanne Stuckey ,  Krzysztof Krajewski ,  Sheng Jiang ,  Peter P Roller ,  Hatice Ozel Abaan ,  York Tomita ,  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: 17034116 DOI: 10.1021/jm060460o
Abstract

A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 Prostate Cancer cells with an IC(50) value of 200 nM and effectively induces Apoptosis in a dose-dependent manner.