The Future of Kinase Drug Discovery

Oncology Drug Discovery and Preclinical Research, Sanofi Oncology, Vitry-sur-Seine, France 

One of the recurrent clinical problems of molecularly targeted kinase inhibitors in oncology has been the inevitable occurrence of resistance on account of point mutations that impair drug binding and hence effective enzymatic 

RSC Drug Discovery Series No. 19 Kinase Drug Discovery 

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Approximately one-third of cellular proteins contain phosphate and are subject to covalent modification by phosphorylation and dephosphorylation reactions. This reversible phosphorylation of proteins causes conformational changes in the protein that dramatically alters their properties, e.g. from an active to an inactive enzyme, or vice versa. The sites of protein phosphorylation are those amino acid residues that contain hydroxyl groups, most commonly serine but also tyrosine and threonine (Fig. 27.2) (Chapter 31). Phosphorylation uses protein kinase and dephosphorylation uses protein phosphatase. The importance of reversible protein phosphorylation to the living cell is emphasised by the fact that protein kinases and protein phosphatases comprise approximately 5% of the proteins encoded by the human genome. Current research is discovering abnormalities of protein phosphorylation that are associated with diseases, notably type 2 diabetes meUitus (T2DM) and cancer. In the future, the discovery of drugs that modify protein phosphorylation/dephosphorylation promises new therapies for the treatment of these diseases. 

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