Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression

  • J Med Chem. 2012 Oct 11;55(19):8502-14. doi: 10.1021/jm3010306.
Jianfang Chen  1 ,  Haibin Zhou ,  Angelo Aguilar ,  Liu Liu ,  Longchuan Bai ,  Donna McEachern ,  Chao-Yie Yang ,  Jennifer L Meagher ,  Jeanne A Stuckey ,  Shaomeng Wang
Affiliations
  • 1. Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
PMID: 23030453 DOI: 10.1021/jm3010306
Abstract

Bcl-2 and Bcl-xL antiapoptotic proteins are attractive Cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K(i) < 1 nM and has low nanomolar IC(50) values in cell growth inhibition in Cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung Cancer xenograft model at a well-tolerated dose schedule.

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