Abstract
Regulating cell function by controlling cell pathways is an important strategy
in the development of agents for the treatment of cancer and numerous other
diseases. Protein kinases are a family of enzymes involved in the regulation
of almost all cell processes. Scientists have identified 518 kinases encoded
by the human genome. By adding phosphate groups to substrate proteins, these
enzymes control the activity, the location, the association of these substrate
proteins with other proteins and their function. Thus kinases play an
essential role in signal transduction and the coordination of complex
functions in particular the cell cycle.
Because alterations in protein phosphorylation are frequently associated with
human disease, investment in the development of pharmacological inhibitors of
protein kinases has grown exponentially. About 30% of existing drug discovery
programs in the pharmaceutical industry target a protein kinase (reviewed in
Cohen, Nature reviews drug discovery, 2002; Fischer & Gianella Borradori, Exp.
Opin. Investig. Drugs, 2005; Grant, Cell. Mol. Life Sci., 2009). Today, dozens
of kinase inhibitors are on the market to treat cancer and the cumulated sales
of the blockbuster drug Gleevec (tyrosine kinase inhibitor, Novartis) was $3.7
billion in 2008 (Novartis annual report 2008). However, no pharmacological
cyclin-dependent kinase inhibitors (CDK, serine/threonine protein kinases), a
key kinase sub-family, have yet reached the market. Although this sub-family
includes 20 members (and 25 cyclins) in humans, a more limited number has been
identified. To constitute active protein kinase complexes (see figure 1), CDKs
are regulated by transient association with a regulatory partner (cyclins), go
through various post-translational modifications (e.g. phosphorylation) and
transient association with a natural inhibitory protein (Cip1, Kip1/2 or
Ink4A-D).
This family is of particular interest because of its essential involvement in
neuronal cell physiology (CDK5), pain signalling (CDK5), apoptosis (CDK1,
CDK2, CDK5), transcription (CDK7, CDK8, CDK9), RNA splicing (CDK11),
differentiation (CDK2, CDK5, CDK6, CDK9) and especially cell cycle control
(CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK10; see figure 2). In addition P.
Nurse, L. Artwell and T. Hunt were awarded the Nobel Prize in
Physiology/Medicine in 2001 for their work in the discovery of the role of
cyclins and CDK in the control of the cell cycle.
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