Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma

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• 作者：Hong Wu ; Wenchao Wang ; Feiyang Liu ; Ellen L. Weisberg ; Bei Tian ; Yongfei Chen ; Binhua Li ; Aoli Wang ; Beilei Wang ; Zheng Zhao ; Douglas W. McMillin ; Chen Hu ; Hong Li ; Jinhua Wang ; Yanke Liang ; Sara J. Buhrlage ; Junting Liang ; Jing Liu ; Guang Yang ; Jennifer R. Brown ; Steven P. Treon ; Constantine S. Mitsiades ; James D. Griffin ; Qingsong Liu ; Nathanael S. Gray
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：May 16, 2014
• 年：2014
• 卷：9
• 期：5
• 页码：1086-1091
• 全文大小：340K
• 年卷期：v.9,no.5(May 16, 2014)
• ISSN：1554-8937

文摘

BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC₅₀ of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC₅₀ of 475 nM, and inhibits phosphorylation of a downstream effector PLC纬2 (Tyr759) with an EC₅₀ of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.