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

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Affiliation

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.

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