title: Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays.
abstract: Cyclin-dependent kinases (CDKs) play important roles in regulating cell cycle progression, and altered cell cycles resulting from over-expression or abnormal activation of CDKs observed in many human cancers. As a result, CDKs have become extensive studied targets for developing chemical inhibitors for cancer therapies; however, protein kinases share a highly conserved ATP binding pocket at which most chemical inhibitors bind, therefore, a major challenge in developing kinase inhibitors is achieving target selectivity. To identify cell growth inhibitors with potential applications in cancer therapy, we used an integrated approach that combines one-pot chemical synthesis in a combinatorial manner to generate diversified small molecules with new chemical scaffolds coupled with growth inhibition assay using developing zebrafish embryos. We report the successful identification of a novel lead compound that displays selective inhibitory effects on CDK2 activity, cancer cell proliferation, and tumor progression in vivo. Our approaches should have general applications in developing cell proliferation inhibitors using an efficient combinatorial chemical genetic method and integrated biological assays. The novel cell growth inhibitor we identified should have potential as a cancer therapeutic agent.
authors.affiliation: Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry, Peking University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yang
authors.forename: Chao
authors.initials: C
authors.lastname: Che
authors.forename: Haixia
authors.initials: H
authors.lastname: Zou
authors.forename: Hanshuo
authors.initials: H
authors.lastname: Yang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Junmin
authors.initials: J
authors.lastname: Quan
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D013379:Substrate Specificity / Q000187:drug effects; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D018844:Cyclin-Dependent Kinases