PUBLICATION
Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays
- Authors
- Xiang, J., Yang, H., Che, C., Zou, H., Yang, H., Wei, Y., Quan, J., Zhang, H., Yang, Z., and Lin, S.
- ID
- ZDB-PUB-090217-6
- 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
-
- Enzyme Inhibitors/analysis
- Enzyme Inhibitors/chemical synthesis
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology
- Growth Inhibitors/analysis*
- Growth Inhibitors/chemical synthesis
- Growth Inhibitors/chemistry
- Growth Inhibitors/pharmacology
- Cell Line, Tumor
- Drug Screening Assays, Antitumor*
- Female
- Cyclin-Dependent Kinases/antagonists & inhibitors
- Computational Biology
- Mice, Nude
- Drug Design
- Combinatorial Chemistry Techniques*
- Cell Proliferation/drug effects
- Mice
- Phenotype
- Zebrafish/metabolism*
- Animals
- Humans
- Neoplasms/pathology*
- Antineoplastic Agents/analysis*
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Models, Molecular
- Substrate Specificity/drug effects
- PubMed
- 19194508 Full text @ PLoS One
Citation
Xiang, J., Yang, H., Che, C., Zou, H., Yang, H., Wei, Y., Quan, J., Zhang, H., Yang, Z., and Lin, S. (2009) Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays. PLoS One. 4(2):e4361.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping