Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor

0343928 - ÚEB 2011 RIV CH eng J - Journal Article
Kryštof, Vladimír - McNae, I. W. - Walkinshaw, M. D. - Fischer, P.M. - Müller, P. - Vojtešek, B. - Orság, Martin - Havlíček, Libor - Strnad, Miroslav
Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor.
Cellular and Molecular Life Sciences. Roč. 62, č. 15 (2005), s. 1763-1771. ISSN 1420-682X. E-ISSN 1420-9071
R&D Projects: GA ČR GP204/03/D231
Institutional research plan: CEZ:AV0Z50380511
Keywords : olomoucine II * roscovitine * cyclin-dependent kinase inhibitor
Subject RIV: CE - Biochemistry
Impact factor: 4.582, year: 2005

The study describes the protein kinase selectivity profile, as well as the binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from co-crystal analysis. Apart from the main cell cycle-regulating kinase CDK2, olomoucine II exerts specificity for CDK7 and CDK9, with important functions in the regulation of RNA transcription. In vitro anticancer activity of the inhibitor in a panel of tumor cell lines shows a wide potency range with a slight preference for cells harboring a wild-type p53 gene. Cell-based assays confirmed activation of p53 protein levels and events leading to accumulation of p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase function. We conclude that perturbations in RNA synthesis may lead to activation of p53 and that this contributes to the antiproliferative potency of cyclin-dependent kinase inhibitors.
Permanent Link: http://hdl.handle.net/11104/0186288