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

نویسندگان

  • 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
چکیده

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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عنوان ژورنال:

دوره 9  شماره 

صفحات  -

تاریخ انتشار 2014