Since the discovery of protein phosphorylation by E. Krebs and E. Fisher in the 1950s, protein kinases have been recognised as major players in cell signalling. Their implication in disease has been extensively validated in cancer, diabetes, cardiovascular disease and central nervous system pathologies. In the pharmaceutical industry, despite initial scepticism on the potential selectivity of adenosine tri-phosphate (ATP) competitor kinase inhibitors, knowledge of the human genome and three-dimensional structure of protein kinases has revealed structural and phylogenetic elements allowing differentiation amongst kinases. Consequently, we can distinguish today classes of kinases according to the selectivity profile of inhibitors in clinical development and drugs in the market. The abundance of available structural data for kinases and inhibitors allows us now to identify key interactions. However, new biding modes are identified leading to increase selectivity of particular compounds. Facing this mount of knowledge and experience on screening for small molecule inhibitors, industry faces several challenges: first, the choice of a kinase as target; secondly, how to obtain molecules with desired selectivity, potency and pharmacokinetics allowing it to be active in patients and thirdly, developing assays for assessing target hitting and patient selection in the clinic. These challenges are key aspects in an increasingly competitive field and an extremely active research area.
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