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

作者：Hong Wu, Wenchao Wang, Feiyang Liu, Ellen Weisberg, Bei Tian, Yongfei Chen, Binhua Li, Aoli Wang, Beilei Wang, Zheng Zhao, Douglas W. McMillin, Hu Chen, 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 · 发表于：ACS Chemical Biology · 年份：2014 · DOI：10.1021/cb4008524 · 被引用次数：76 · 研究领域：Chronic Lymphocytic Leukemia Research、Lymphoma Diagnosis and Treatment、Chronic Myeloid Leukemia Treatments

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.