Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor
Language English Country Switzerland Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16003486
PubMed Central
PMC11139129
DOI
10.1007/s00018-005-5185-1
Knihovny.cz E-resources
- MeSH
- Cyclin-Dependent Kinase 2 MeSH
- Transcription, Genetic MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Growth Inhibitors chemistry pharmacology MeSH
- Nuclear Proteins metabolism MeSH
- CDC2-CDC28 Kinases antagonists & inhibitors chemistry MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Protein p53 metabolism MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Proto-Oncogene Proteins c-mdm2 MeSH
- Proto-Oncogene Proteins metabolism MeSH
- Purines chemistry pharmacology MeSH
- Ribosomal Proteins metabolism MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CDK2 protein, human MeSH Browser
- Cyclin-Dependent Kinase 2 MeSH
- Enzyme Inhibitors MeSH
- Growth Inhibitors MeSH
- Nuclear Proteins MeSH
- CDC2-CDC28 Kinases MeSH
- MDM2 protein, human MeSH Browser
- Tumor Suppressor Protein p53 MeSH
- olomoucine II MeSH Browser
- Antineoplastic Agents MeSH
- Proto-Oncogene Proteins c-mdm2 MeSH
- Proto-Oncogene Proteins MeSH
- Purines MeSH
- ribosomal protein L11 MeSH Browser
- Ribosomal Proteins MeSH
The study describes the protein kinase selectivity profile, as well as the binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2, olomoucine II exerts specificity for CDK7 and CDK9, with important functions in the regulation of RNA transcription. In vitro anticancer activity of the inhibitor in a panel of tumor cell lines shows a wide potency range with a slight preference for cells harboring a wild-type p53 gene. Cell-based assays confirmed activation of p53 protein levels and events leading to accumulation of p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase function. We conclude that perturbations in RNA synthesis may lead to activation of p53 and that this contributes to the antiproliferative potency of cyclindependent kinase inhibitors.
References provided by Crossref.org
The inhibitor of cyclin-dependent kinases, olomoucine II, exhibits potent antiviral properties