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