Open AccessDiscovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma
Author(s) -
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
Publication year - 2014
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/cb4008524
Subject(s) - bruton's tyrosine kinase , kinome , autophosphorylation , tyrosine kinase , kinase , b cell , phosphorylation , b cell receptor , cancer research , microbiology and biotechnology , chemistry , biochemistry , signal transduction , biology , protein kinase a , antibody , immunology
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.
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