title: Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma.
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.
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.forename: Bei
authors.initials: B
authors.lastname: Tian
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Chen
authors.forename: Binhua
authors.initials: B
authors.lastname: Li
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Yanke
authors.initials: Y
authors.lastname: Liang
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Buhrlage
authors.forename: Junting
authors.initials: J
authors.lastname: Liang
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human