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

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

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Title: Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma
Author: Wu, Hong; Wang, Wenchao; Liu, Feiyang; Weisberg, Ellen L.; Tian, Bei; Chen, Yongfei; Li, Binhua; Wang, Aoli; Wang, Beilei; Zhao, Zheng; McMillin, Douglas W.; Hu, Chen; Li, Hong; Wang, Jinhua; Liang, Yanke; Buhrlage, Sara J.; Liang, Junting; Liu, Jing; Yang, Guang; Brown, Jennifer R.; Treon, Steven P.; Mitsiades, Constantine S.; Griffin, James D.; Liu, Qingsong; Gray, Nathanael S.

Note: Order does not necessarily reflect citation order of authors.

Citation: Wu, H., W. Wang, F. Liu, E. L. Weisberg, B. Tian, Y. Chen, B. Li, et al. 2014. “Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma.” ACS Chemical Biology 9 (5): 1086-1091. doi:10.1021/cb4008524.
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Abstract: 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 PLCγ2 (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.
Published Version: doi:10.1021/cb4008524
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