Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer
ACS Chemical Biology2013Vol. 8(7), pp. 1423–1428
Citations Over TimeTop 13% of 2013 papers
Feiyang Liu, Xin Zhang, Ellen Weisberg, Sen Chen, Wooyoung Hur, Wu Hong, 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
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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