title: Discovery of novel purine derivatives with potent and selective inhibitory activity against c-Src tyrosine kinase.
abstract: We report here the discovery of novel purine derivatives with potent and selective inhibitory activity against c-Src tyrosine kinase by adopting a strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and bioassay. Thirty two compounds were selected and synthesized. All compounds showed potent inhibitory activity against c-Src kinase with IC₅₀ values ranging from 3.14 μM to 0.02 μM. Compound 5i was identified as one of the most potent agent with an IC₅₀ 120 times lower than those of the hits. The high hit rate (100%) and the potency of the new Src kinase inhibitors demonstrated the efficiency of the strategy for the focused library design and virtual screening. The novel active chemical entities reported here should be good leads for further development of purine-based anticancer drugs targeting Src tyrosine kinase.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Jingui
authors.initials: J
authors.lastname: Ma
authors.forename: Jianmei
authors.initials: J
authors.lastname: Shi
authors.forename: Linghua
authors.initials: L
authors.lastname: Meng
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D009025:Morpholines; C559231:N-(4-aminosulfonylphenyl)-2-morpholino-9H-purin-6-amine; D047428:Protein Kinase Inhibitors; D011687:Purines; D019061:src-Family Kinases; C030985:purine