Novel approaches for the identification of allosteric inhibitors of high value therapeutic targets

Protein kinases, protein phosphatases and small G-proteins are of enormous interest to the pharmaceutical industry. They are key controllers of intracellular signalling and cellular homeostasis, and inappropriate levels of their activity are fundamental to a wide range of diseases, including many cancers. To-date a range of inhibitors has been developed against protein kinases and, to a lesser extent, protein phosphatases and small G-proteins but numerous issues remain. One of the primary difficulties for protein kinases and small G-proteins is the dominant effect of the nucleotide binding sites on ligand affinity, which has skewed efforts towards nucleotide mimics. However, the lack of selectivity of nucleotide mimics is the Achilles heel of kinase drug discovery, because of the homology of the co-factor binding sites across the protein sub-families. Innovation requires a workflow that delivers selective kinase inhibitors with confidence. Correspondingly, there is great current interest in the sector in identifying allosteric sites, which inhibit these enzymes without binding in the nucleotide or substrate binding sites. Such sites have a far greater likelihood to be specific for individual enzymes and to be targetable by inhibitors with the required properties for clinical use.