Discovery of a selective irreversible BMX inhibitor for prostate cancer

  • ACS Chem Biol. 2013 Jul 19;8(7):1423-8. doi: 10.1021/cb4000629.
Feiyang Liu  1 ,  Xin Zhang ,  Ellen Weisberg ,  Sen Chen ,  Wooyoung Hur ,  Hong Wu ,  Zheng Zhao ,  Wenchao Wang ,  Mao Mao ,  Changmeng Cai ,  Nicholas I Simon ,  Takaomi Sanda ,  Jinhua Wang ,  A Thomas Look ,  James D Griffin ,  Steven P Balk ,  Qingsong Liu ,  Nathanael S Gray
Affiliations
  • 1. High Magnetic Field laboratory, Chinese Academy of Sciences , P.O. Box 1110, Hefei, Anhui 230031, P. R. China.
PMID: 23594111 DOI: 10.1021/cb4000629
Abstract

BMX is a member of the Tec family of nonreceptor tyrosine Kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX Kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of Prostate Cancer cell lines. Using a combinatorial kinase inhibitor screening strategy, we discovered that the allosteric Akt Inhibitor, MK2206, is able to potentiate BMX inhibitor's antiproliferation efficacy against Prostate Cancer cells.