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

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.