Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity

0368592 - ÚEB 2012 RIV US eng J - Journal Article
Jorda, Radek - Havlíček, Libor - McNae, I. W. - Walkinshaw, M. D. - Voller, Jiří - Šturc, Antonín - Navrátilová, Jana - Kuzma, Marek - Mistrik, M. - Bártek, J. - Strnad, Miroslav - Kryštof, Vladimír
Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity.
Journal of Medicinal Chemistry. Roč. 54, č. 8 (2011), s. 2980-2993. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GA301/02/0475; GA ČR GA301/08/1649; GA MŠMT ED0007/01/01
Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z50200510
Keywords : STRUCTURE-GUIDED DESIGN * DNA-END RESECTION * DOWN-REGULATION * R-ROSCOVITINE * CELL-CYCLE
Subject RIV: ED - Physiology
Impact factor: 5.248, year: 2011

Inhibition of cyclin-dependent kinases (CDKs) with. small molecules has been suggested as a strategy for treatment of cancer, based on deregulation of CDKs commonly found in many types of human tumors. Here, a new potent CDK2 inhibitor with pyrazolo[4,3-d]pyrimidine scaffold has been synthesized, characterized, and evaluated in cellular and biochemical assays. 7-Benzylamino-5(R)-[2-(hydroxymethyl)-propyl]amino-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine, compound 7, was prepared as a bioisostere of the well-known CDK inhibitor roscovitine. An X-ray crystal structure of compound 7 bound to CDK2 has been determined, revealing a binding mode similar to that of roscovitine.
Permanent Link: http://hdl.handle.net/11104/0202891