A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors

0399222 - ÚEB 2014 RIV US eng J - Journal Article
Gucký, T. - Jorda, Radek - Zatloukal, M. - Bazgier, V. - Berka, K. - Řezníčková, Eva - Béres, T. - Strnad, Miroslav - Kryštof, Vladimír
A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors.
Journal of Medicinal Chemistry. Roč. 56, č. 15 (2013), s. 6234-6247. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GAP305/12/0783; GA ČR GD203/09/H046
Grant - others:GA MŠk(CZ) ED0007/01/01; GA MŠk(CZ) ED2.1.00/03.0058; GA MŠk(CZ) EE2.3.20.0017
Program: ED; ED; EE
Institutional research plan: CEZ:AV0Z50380511
Keywords : CHRONIC LYMPHOCYTIC-LEUKEMIA * DINACICLIB SCH 727965 * CELL-CYCLE
Subject RIV: ED - Physiology
Impact factor: 5.480, year: 2013

The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.
Permanent Link: http://hdl.handle.net/11104/0226634