Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer
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- 作者：Feiyang Liu ; 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
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：July 19, 2013
- 年：2013
- 卷：8
- 期：7
- 页码：1423-1428
- 全文大小：331K
- 年卷期：v.8,no.7(July 19, 2013)
- ISSN：1554-8937
文摘
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鈥檚 antiproliferation efficacy against prostate cancer cells.