title: Discovery of a selective irreversible BMX inhibitor for prostate cancer.
abstract: BMX is a member of the TEC family of nonreceptor tyrosine kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of prostate cancer cell lines. Using a combinatorial kinase inhibitor screening strategy, we discovered that the allosteric Akt inhibitor, MK2206, is able to potentiate BMX inhibitor's antiproliferation efficacy against prostate cancer cells.
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences , P.O. Box 1110, Hefei, Anhui 230031, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Simon
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000592892:BMX-IN-1; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D013449:Sulfonamides; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases