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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
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SYSNO ASEP 0454968 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 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 (UEB-Q) RID, ORCID
Weitensteiner, S. (DE)
Havlíček, Libor (UEB-Q) RID, ORCID
Jorda, Radek (UEB-Q) ORCID, RID
Gucký, Tomáš (UEB-Q) ORCID
Berka, K. (CZ)
Bazgier, Václav (UEB-Q) ORCID, RID
Zahler, S. (DE)
Kryštof, Vladimír (UEB-Q) RID, ORCID
Strnad, Miroslav (UEB-Q) RID, ORCIDSource Title Chemical Biology & Drug Design. - : Wiley - ISSN 1747-0277
Roč. 86, č. 6 (2015), s. 1528-1540Number of pages 13 s. Language eng - English Country GB - United Kingdom Keywords angiogenesis ; apoptosis ; aurora A Subject RIV CE - Biochemistry R&D Projects GAP305/12/0783 GA ČR - Czech Science Foundation (CSF) GA14-19590S GA ČR - Czech Science Foundation (CSF) LO1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UEB-Q - RVO:61389030 UT WOS 000367376800022 DOI 10.1111/cbdd.12618 Annotation 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2016 Electronic address http://gateway.isiknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=CCC&DestLinkType=FullRecord&UT=000367376800022
Number of the records: 1