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Protein kinases — the major drug targets of the twenty-first century?

Abstract

Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

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Figure 1
Figure 2: Chemical structures of some small-molecule inhibitors of protein kinases that have been approved or are undergoing human clinical trials.
Figure 3: Basis for the specificity of two ATP-competitive protein-kinase inhibitors.

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Acknowledgements

I thank J. Adams, S. Cartlidge, R. Ford, S. Jakes, B. Machin and N. Lydon for helpful discussions. I apologise to the many scientists whose important discoveries could not be included or referenced in this article because of space restrictions. The work carried out in my laboratory is supported by the UK Medical Research Council, The Royal Society of London, Diabetes UK, The Louis Jeantet Foundation, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk and Pfizer.

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DATABASES

Cancer.gov

breast cancer

chronic myelogenous leukaemia

colon tumour

gastrointestinal stromal cancer

lung cancer

LocusLink

ABL

BCR

calcineurin

calmodulin

CDK2

CHK1

cyclophilin

EGF

EGFR

FGFR

FKBP

IL-1

IL-2

JNK

c-KIT

MKK1

MLK

p38 MAPK

mTOR

PDGF

PDGF receptor

PKA

PKC

PKC-β

PtdIns 3-kinase

PTEN

RAF

ROCK

TNF

VEGF

VEGFR

Medscape DrugInfo

Cyclosporin

Gleevec

OMIM

chronic myelogenous leukaemia

insulin-dependent diabetes mellitus

inflammatory bowel disease

rheumatoid arthritis

<i>Saccharomyces</i> Genome Database

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FURTHER INFORMATION

Encyclopedia of Life Sciences

protein kinases

National Cancer Institute

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Cohen, P. Protein kinases — the major drug targets of the twenty-first century?. Nat Rev Drug Discov 1, 309–315 (2002). https://doi.org/10.1038/nrd773

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