Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

As described in the previous chapter, most kinase inhibitors that have been developed for use in the clinic act by blocking ATP binding; however, there is growing interest in identifying compounds that target kinase activities and functions without interfering with the conserved features of the ATP-binding site. This chapter will highlight alternative approaches that exploit unique kinase structural features that are being targeted to identify more selective and potent inhibitors. The figure below, adapted from (Sammons et al., Molecular Carcinogenesis 58:1551–1570, 2019), provides a graphical description of the various approaches to manipulate kinase activity. In addition to the type I and II inhibitors, type III kinase inhibitors have been identified to target sites adjacent to the ATP-binding site in the catalytic domain. New information on kinase structure and substrate-binding sites has enabled the identification of type IV kinase inhibitor compounds that target regions outside the catalytic domain. The combination of targeting unique allosteric sites outside the catalytic domain with ATP-targeted compounds has yielded a number of novel bivalent type V kinase inhibitors. Finally, emerging interest in the development of irreversible compounds that form selective covalent interactions with key amino acids involved in kinase functions comprise the class of type VI kinase inhibitors.