title: Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening.
abstract: Inhibition of BCR-ABL tyrosine kinase activity has shown to be essential for the treatment of chronic myelogenous leukemia (CML). However, drug resistance has quickly arisen in recent clinical trials for STI571 (Gleevec), which is the first approved drug of CML by inhibiting ABL tyrosine kinase. It is desirable to develop new types of ABL tyrosine kinase inhibitors that may overcome this drug resistance problem. Here we present the discovery of novel inhibitors targeted at the catalytic domain of ABL tyrosine kinase by using three-dimensional database searching techniques. From a database containing 200,000 commercially available compounds, the top 1000 compounds with the best DOCK energy score were selected and subjected to structural diversity and drug likeness analysis, 15 compounds were submitted for biological assay. Eight out of the 15 showed inhibitory activity against K562 cells with IC(50) value ranging from 10 to 200 microM. Two promising compounds showed inhibition in further ABL tyrosine phosphorylation assay. It is anticipated that those two compounds can serve as lead compounds for further drug design and optimization.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Chunzheng
authors.initials: C
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D030541:Databases, Genetic; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D004791:Enzyme Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C022616:thiazolyl blue