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

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2014 Feb 22

PMID 24556163

Citations 28

Authors

Hong Wu

Wenchao Wang

Feiyang Liu

Ellen L Weisberg

Bei Tian

Yongfei Chen

Binhua Li

Aoli Wang

Beilei Wang

Zheng Zhao

Douglas W McMillin

Chen Hu

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

Affiliations

Soon will be listed here.

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.

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