Characterization of a Pyrazolo[4,3-d]pyrimidine Inhibitor of Cyclin-Dependent Kinases 2 and 5 and Aurora A With Pro-Apoptotic and Anti-Angiogenic Activity In Vitro
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26198005
DOI
10.1111/cbdd.12618
Knihovny.cz E-resources
- Keywords
- angiogenesis, apoptosis, aurora A, cyclin-dependent kinase, inhibitor, pyrazolo[4,3-d]pyrimidine,
- MeSH
- Apoptosis drug effects MeSH
- Aurora Kinase A antagonists & inhibitors MeSH
- Cell Cycle drug effects MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors MeSH
- Cyclin-Dependent Kinase 5 antagonists & inhibitors MeSH
- Human Umbilical Vein Endothelial Cells MeSH
- HCT116 Cells MeSH
- Cyclin-Dependent Kinase Inhibitor Proteins chemical synthesis chemistry pharmacology MeSH
- Angiogenesis Inhibitors chemical synthesis chemistry pharmacology MeSH
- Protein Kinase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Design MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- AURKA protein, human MeSH Browser
- Aurora Kinase A MeSH
- CDK2 protein, human MeSH Browser
- CDK5 protein, human MeSH Browser
- Cyclin-Dependent Kinase 2 MeSH
- Cyclin-Dependent Kinase 5 MeSH
- Cyclin-Dependent Kinase Inhibitor Proteins MeSH
- Angiogenesis Inhibitors MeSH
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT-116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti-angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis-like activity in endothelial cells offers possible therapeutic potential.
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