Protein Kinases are key elements of all metabolic pathways.

Phosphorylation is the addition of a phosphate group (PO4) to a molecule. Phosphorylation of proteins on their Serine, Threonine and Tyrosine residues, by protein kinases, is considered as one of the main mechanisms universally used by cells to finely tune their metabolic and regulatory pathways. Essentially all important physiological phenomena are regulated by phosphorylation reactions, performed by a complex mosaic of 518 different proteins in man.

The Human Kinome

Image: The human kinome comprises 40 atypical PKs and 478 classical PKs. The latter consist of 388 serine/threonine kinases, 90 tyrosine kinases and 50 sequences which lack a functional catalytic sites. (Manning et al., Science, 6 December 2002) Download a larger version.

Since their initial discovery, human protein kinases have been the object of extensive research in all possible areas of biology, physiology and medicine. The importance of protein phosphorylation has been highlighted by the attribution of three Nobel Awards in Physiology and Medicine:

  • In 1992, to Edwin G. Krebs and Edmond H. Fisher, the discovery of the protein kinases.
  • In 2000, to Paul Greengard, for his work on the essential functions of phosphorylation in the intracellular transduction and signaling mechanisms of neurotransmitters in the brain.
  • In 2001, to Paul Nurse, Lee Hartwell and Tim Hunt, for their identification of the essential role of cyclin-dependent kinases (CDKs) in the cell division cycle.

Directly or indirectly, more than 400 human diseases have been connected to protein kinases. Aberrant kinase activity is implicated in a variety of diseases, in particular those involving inflammatory or proliferative responses, such as cancer, rheumatoid arthritis, cardiovascular and neurological disorders, asthma and psoriasis. Therefore, major efforts are done in the search for pharmacological inhibitors of protein kinases and their subsequent optimization, characterization and pre-clinical and clinical evaluation.

These efforts have been strongly encouraged by the clinical successes of the first marketed small molecule PK inhibitors such as Novartis’ Gleevec™, for the treatment of chronic myeloid leukemia and other maligancies (e.g. GIST). The Gleevec success has been followed by the recent approval of several PKIs, for instance Pfizer’s Sutent™, GSK’s Tykerb™, BMS’ Sprycel™ or Novartis’ Tasigna™. Kinase inhibitors now make up a significant fraction (> 30%) of most major pharmaceutical companies’ pipelines and are found to be in development against: