J. Biol. Chem. 280, 31208-31219.
Bach,
S., Knockaert, M., Lozach, O., Reinhardt, J., Baratte, B., Schmitt, S.,
Coburn, S.P., Tang, L., Jiang. T., Liang, D.C., Galons, H., Dierick, J.F.,
Totzke, F., Schächtele, C., Lerman, A.S., Carnero, A., Wan, Y., Gray, N. and
Meijer, L.
Correspondence: Laurent Meijer
Tel.: 33-0-2-98-29-23-39; Fax: 33-0-2-98-29-23-42; E-mail:
Prof. Laurent Meijer
(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.
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