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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Řezníčková
authors.affiliation: Department of Pharmacy, LMU Munich - Center for Drug Research - Pharmaceutical Biology, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Weitensteiner
authors.affiliation: Isotope Laboratory, Institute of Experimental Botany ASCR, Vídeňská 1083, 14220, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Havlíček
authors.affiliation: 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.
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.affiliation: 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.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Gucký
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 77146, Olomouc, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Berka
authors.affiliation: 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.|Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 771 46, Olomouc, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Bazgier
authors.affiliation: Department of Pharmacy, LMU Munich - Center for Drug Research - Pharmaceutical Biology, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.affiliation: 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.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
authors.affiliation: 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.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D047428:Protein Kinase Inhibitors; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051360:Cyclin-Dependent Kinase 5; C495894:CDK2 protein, human; C495905:CDK5 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: angiogenesis; apoptosis; aurora A; cyclin-dependent kinase; inhibitor; pyrazolo[4,3-d]pyrimidine