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

  • ACS Chem Biol. 2014 May 16;9(5):1086-91. doi: 10.1021/cb4008524.
Hong Wu  1 ,  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
  • 1. High Magnetic Field laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.
PMID: 24556163 DOI: 10.1021/cb4008524
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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