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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
Author(s) -
Řezníčková Eva,
Weitensteiner Sabine,
Havlíček Libor,
Jorda Radek,
Gucký Tomáš,
Berka Karel,
Bazgier Václav,
Zahler Stefan,
Kryštof Vladimír,
Strnad Miroslav
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12618
Subject(s) - cyclin dependent kinase , kinase , cdk inhibitor , microbiology and biotechnology , polo like kinase , cell cycle , angiogenesis , cancer research , chemistry , biology , apoptosis , biochemistry
Selective inhibitors of kinases that regulate the cell cycle, such as cyclin‐dependent kinases ( CDK s) 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 CDK 2 inhibitory and antiproliferative activities. A new compound, 2i , which preferentially inhibits CDK 2, CDK 5, 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 CDK 5 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.