2区 · 生物学
Letter
作者: Hu, Chen ; Wang, Wenchao ; Liu, Feiyang ; Li, Hong ; Wang, Jinhua ; Wang, Beilei ; Tian, Bei ; Liu, Qingsong ; Buhrlage, Sara J. ; Griffin, James D. ; Li, Binhua ; Zhao, Zheng ; Liu, Jing ; Brown, Jennifer R. ; Wu, Hong ; Treon, Steven P. ; McMillin, Douglas W. ; Liang, Junting ; Gray, Nathanael S. ; Chen, Yongfei ; Liang, Yanke ; Weisberg, Ellen L. ; Wang, Aoli ; Yang, Guang ; Mitsiades, Constantine S.
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.