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Pharmacological inhibitors of DISEASE-RELEVANT CYCLIN-dEPENDENT
PROTEIN KINASES (CDks) and GLYCOGEN SYNTHASE KINASE -3 (GSK-3)
Laurent MEIJER
Cell Cycle Laboratory, Station Biologique de Roscoff, C.N.R.S., BP 74, 29682
ROSCOFF cedex, Bretagne, France. E-mail: meijer@sb-roscoff.fr
(http://www.sb-roscoff.fr/CyCell/)
Phosphorylation represents one the most common post-translational mechanism used by cells
to regulate their enzymatic and structural proteins. Frequent alteration of protein
phosphorylation in human disease is the reason for an exponentially growing investment in
the optimization and therapeutic evaluation of small molecular weight, pharmacological
inhibitors of protein kinases, the enzymes responsible for protein phosphorylation. It is
estimated that nowadays 30-35 % of drug discovery programs in the pharmaceutical industry
target a protein kinase! Currently 55 kinase inhibitors are undergoing clinical evaluation
against diseases such as cancers, inflammation, diabetes, neurodegeneration.
Among the 518 human protein kinases we have selected a few disease-relevant kinases to
screen for small molecular weight inhibitors. Among these, cyclin-dependent kinases (CDKs)
regulate the cell division cycle, apoptosis, transcription, differentiation, nervous system
functions, and GSK-3, an essential element of the Wnt signaling pathway, is involved in
multiple physiological processes including cell cycle regulation by controlling the levels of
cyclin D1 and -catenin, insulin action on glycogen synthesis, axonal outgrowth, neuronal
cell death. Both families of enzymes regulate -amyloid formation and tau
hyperphosphorylation, two hallmarks of Alzheimer’s disease. Inhibitors of these kinases have
a strong potential to treat cancers, neurodegenerative diseases (Alzheimer’s, Parkinson’s,
Nieman-Pick type III, stroke, etc…), unicellular parasites. Some of our early CDK/GSK-3
inhibitors have reached the pre-clinical and clinical stages of pharmaceutical evaluation. For
instance, roscovitine (CYC202, Seliciclib), is currently undergoing phase 2 clinical trials
against leukaemia, lung and breast cancers, and phase 1 trials against various kidney diseases.
It is undergoing pre-clinical animal evaluation against Alzheimer’s disease stroke and
Niemann-Pick’s disease type III. Several other families of kinase inhibitors are currently
being developed in the laboratory, a special focus on the bis-indole indirubins will be
provided.
Over a hundred CDK inhibitors [1] and about thirty GSK-3 inhibitors [2] have been
identified, among which more than forty have been co-crystallized with CDK2 or CDK5 and
four with GSK-3. These co-crystal structures are extremely helpful to design further
derivatives with increased potency and selectivity. These kinase inhibitors all target the ATPbinding
pocket of the catalytic site of their targets. The actual selectivity of most compounds,
and thus the underlying mechanism of their cellular effects, is poorly known. We have
developed affinity chromatography using immobilized inhibitors as a straightforward
approach to identify the actual targets of kinase inhibitors [3,4]. Results show that although
some compounds are quite selective, single target products are very unlikely to be discovered.
This may in fact turn out to be an advantage as cells are unlikely to develop resistance to
multiple target drugs.
[1] Knockaert, M., Greengard, P. and Meijer, L., 2002. Pharmacological inhibitors of cyclindependent
kinases. Trends Pharmacol. Sci. 23, 417-425.
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