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Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases

    Sandra W Cowan-Jacob

    * Author for correspondence

    Novartis Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

    ,
    Wolfgang Jahnke

    Novartis Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland

    &
    Stefan Knapp

    Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK

    Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute, Roosevelt Drive, Oxford, OX3 7FZ, UK

    Published Online:https://doi.org/10.4155/fmc.13.216

    Protein kinases are involved in many essential cellular processes and their deregulation can lead to a variety of diseases, including cancer. The pharmaceutical industry has invested heavily in the identification of kinase inhibitors to modulate these disease-promoting pathways, resulting in several successful drugs. However, the field is challenging as it is difficult to identify novel selective inhibitors with good pharmacokinetic/pharmacodynamic properties. In addition, resistance to kinase inhibitor treatment frequently arises. The identification of non-ATP site targeting (‘allosteric’) inhibitors, the identification of kinase activators and the expansion of kinase target space to include the less studied members of the family, including atypical- and pseudo-kinases, are potential avenues to overcome these challenges. In this perspective, the opportunities and challenges of following these approaches and others will be discussed.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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