ZFIN ID: ZDB-PUB-090217-6
Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays
Xiang, J., Yang, H., Che, C., Zou, H., Yang, H., Wei, Y., Quan, J., Zhang, H., Yang, Z., and Lin, S.
Date: 2009
Source: PLoS One   4(2): e4361 (Journal)
Registered Authors: Lin, Shuo
Keywords: Kinase inhibitors, Embryos, Zebrafish, Cell cycle and cell division, Cell cycle inhibitors, Cyclins, Cell proliferation, Hydrogen bonding
MeSH Terms:
  • Animals
  • Antineoplastic Agents/analysis*
  • Antineoplastic Agents/chemical synthesis
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Combinatorial Chemistry Techniques*
  • Computational Biology
  • Cyclin-Dependent Kinases/antagonists & inhibitors
  • Drug Design
  • Drug Screening Assays, Antitumor*
  • Enzyme Inhibitors/analysis
  • Enzyme Inhibitors/chemical synthesis
  • Enzyme Inhibitors/chemistry
  • Enzyme Inhibitors/pharmacology
  • Female
  • Growth Inhibitors/analysis*
  • Growth Inhibitors/chemical synthesis
  • Growth Inhibitors/chemistry
  • Growth Inhibitors/pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasms/pathology*
  • Phenotype
  • Substrate Specificity/drug effects
  • Zebrafish/metabolism*
PubMed: 19194508 Full text @ PLoS One
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.