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J. Biol. Chem., Vol. 280, Issue 35, 31208-31219, September 2, 2005

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Roscovitine Targets, Protein Kinases and Pyridoxal Kinase^*

From the ^aCNRS, Cell Cycle Group, UPS 2682 & UMR 2775, Station Biologique, BP 74, 29682 Roscoff cedex, Bretagne, France, the ^bDepartment of Chemistry, Indiana University-Purdue University, Fort Wayne, Indiana 46805-1499, the ^cNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China, the ^dLaboratoire de Chimie Organique 2, Université René Descartes, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France, the ^eProteomics Unit, BioVallée, Rue Adrienne Bolland, 6041 Gosselies, Belgium, the ^fDipartimento di Chimica Biologica, Università di Padova, 35121 Padova, Italy, the ^gProQinase GmbH, Breisacher Strasse 117, 79106 Freiburg, Germany, the ^hCentro Nacional de Investigaciones Oncologicas (CNIO), Programa de Terapias Experimentales, c/Melchor Fernandez Almagro No. 3, 28029 Madrid, Spain, and the ⁱGenomics Institute of the Novartis Research Foundation, Department of Chemistry, San Diego, California 92121

(R)-Roscovitine (CYC202) is often referred to as a "selective inhibitor of cyclin-dependent kinases." Besides its use as a biological tool in cell cycle, neuronal functions, and apoptosis studies, it is currently evaluated as a potential drug to treat cancers, neurodegenerative diseases, viral infections, and glomerulonephritis. We have investigated the selectivity of (R)-roscovitine using three different methods: 1) testing on a wide panel of purified kinases that, along with previously published data, now reaches 151 kinases; 2) identifying roscovitine-binding proteins from various tissue and cell types following their affinity chromatography purification on immobilized roscovitine; 3) investigating the effects of roscovitine on cells deprived of one of its targets, CDK2. Altogether, the results show that (R)-roscovitine is rather selective for CDKs, in fact most kinases are not affected. However, it binds an unexpected, non-protein kinase target, pyridoxal kinase, the enzyme responsible for phosphorylation and activation of vitamin B₆. These results could help in interpreting the cellular actions of (R)-roscovitine but also in guiding the synthesis of more selective roscovitine analogs.

Received for publication, January 21, 2005 , and in revised form, June 21, 2005.

^* This work was supported by the Ministère de la Recherche/INSERM/CNRS "Molécules et Cibles Thérapeutiques" Program (to L. M.), EEC Grant FP6-2002-Life Sciences & Health, the PRO-KINASE Research Project (to L. M.), Canceropole Grand-Ouest (to L. M.), and Chinese Academy of Sciences Grants (KSCX1-SW-17 and KJCX2-SW-N06) (to T. J. and D. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains additional text and Tables S1 and S2.

^j To whom correspondence should be addressed. Tel.: 33-0-2-98-29-23-39; Fax: 33-0-2-98-29-23-42; E-mail: meijer{at}sb-roscoff.fr.

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