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ACS Chem Biol. 2014 May 16;9(5):1086-91. doi: 10.1021/cb4008524. Epub 2014 Mar 17.

Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma.

Author information

1
High Magnetic Field laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.

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.

PMID:
24556163
PMCID:
PMC4027949
DOI:
10.1021/cb4008524
[Indexed for MEDLINE]
Free PMC Article

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