CHAPTER 3: The Screening and Design of Allosteric Kinase Inhibitors

Allosteric kinase inhibitors are commonly defined as ligands that bind to a region that does not overlap with the ATP-binding pocket, which is utilized by the vast majority of disclosed kinase inhibitors. Allosteric inhibitors have the potential to achieve high potency in a physiological environment and may expand the current therapeutic applications of kinase inhibitors owing to an improved selectivity profile. This chapter summarizes and exemplifies approaches used for the screening and the subsequent design of allosteric small molecule kinase inhibitors. The early discovery of allosteric kinase inhibitors was mostly serendipitous, whilst more recent efforts have been devoted to establishing appropriate assays involving high ATP concentration screening for the specific aim of identifying allosteric inhibitors. Depending on the structural features of kinases and conformational changes required between activation/inactivation states, specifically designed methods are also emerging to accelerate the discovery of allosteric inhibitors.