title: [Molecular design and biological activity of BCR-ABL tyrosine kinase inhibitors].
abstract: OBJECTIVE
  To discover BCR-ABL tyrosine kinase inhibitors through structure based virtual screening.
  
  
  METHODS
  Docking screening against the distinctive inactive conformation of the catalytic domain of BCR-ABL tyrosine kinase was performed on 3D database. The MTT assay was performed to assess the viability of the tumor cells treated with selected compounds. The amount and kinase activity of BCR-ABL protein were detected in the presence of compounds by Western blot analysis and immunoprecipitation.
  
  
  RESULTS
  From the top 1,000 compounds with the best DOCK energy score, 15 compounds were selected for biological assay. Eight out of 15 compounds showed notable inhibitory activity against Ph+ human K562 cells with IC50 values ranging from 10 to 200 micromol/L. In cell-based assays of ABL tyrosine phosphorylation, the ability of two kinds of novel, structurally diverse, lead compounds to inhibit ABL kinase activity was observed. However, no significant differences in the amount of BCR-ABL protein were noted on the ABL immunoblot in the presence of these lead compounds.
  
  
  CONCLUSIONS
  Two promising lead compounds were discovered to inhibit BCR-ABL tyrosine kinase activity. Virtual screening technique has been proven to narrow down the size of screening compound libraries to the most prospective drug candidates with high success rates.
authors.affiliation: State Key Laboratory of Hematology, Institute of Hematology, CAMS and PUMC, Tianjin 300020, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Jian-xiang
authors.initials: JX
authors.lastname: Wang
authors.forename: Chun-zheng
authors.initials: CZ
authors.lastname: Yang
mesh_terms: D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl