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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

E. Řezníčková, S. Weitensteiner, L. Havlíček, R. Jorda, T. Gucký, K. Berka, V. Bazgier, S. Zahler, V. Kryštof, M. Strnad,

. 2015 ; 86 (6) : 1528-40. [pub] 20150916

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc17001087

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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$a Weitensteiner, Sabine $u Department of Pharmacy, LMU Munich - Center for Drug Research - Pharmaceutical Biology, Butenandtstr. 5-13, 81377, Munich, Germany.
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$a Berka, Karel $u Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 77146, Olomouc, Czech Republic.
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$a Zahler, Stefan $u Department of Pharmacy, LMU Munich - Center for Drug Research - Pharmaceutical Biology, Butenandtstr. 5-13, 81377, Munich, Germany.
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$a Kryštof, Vladimír $u Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371, Olomouc, Czech Republic.
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