Protein kinases are the enzymes that catalyzes the transfer of γ-phosphate group from ATP to protein residues containing hydroxyl groups and has an important role in cell growth, proliferation, and differentiation. The human kinome comprises ~535 protein kinases. Mutations / Dysregulation of protein kinases are linked to various diseases, particularly in cancer, also protein kinases are the most widely studied cancer therapeutic targets, with a large number of protein kinase inhibitors are approved in Cancer and another large numbers are in active development.
Further, according to the substrate residues, protein kinases can be classified as tyrosine kinases (including both receptor and nonreceptor tyrosine kinases), serine/threonine kinases, and tyrosine kinase-like enzymes.
Similarly, Kinase Inhibitors can be classified into different categories by using many ways. According to classification system based upon the structures of their drug-enzyme complexes proposed by Roskoski (in 2016), protein kinase inhibitors are classified into six types (Type-I–VI).
Type-I inhibitors bind to the active conformation of the kinase (DFG-Asp in, αC-helix in). Type-I½ inhibitors bind to a DFG-Asp in inactive kinase conformation with αC-helix out, while type-II inhibitors bind to a DFG-Asp out inactive conformation. These types of inhibitors occupy part of the adenine binding pocket and form hydrogen bonds with the hinge region connecting the small and large lobes of the enzyme. Among them, type-I½ and type-II antagonists can be further divided into A and B subtypes. Type A inhibitors extend past the Sh2 gatekeeper residue into the back cleft, while type B inhibitors fail to extend into the back cleft. The possible importance of this difference is that type A inhibitors have longer residence times compared with type B inhibitors when binding to their targets. Type III and type IV kinase inhibitors are allosteric in nature. Type III inhibitors restrain kinase activity by binding to an allosteric site, which is in the cleft between the small and large kinase lobes adjacent to the ATP-binding pocket.
Contrariwise, type IV inhibitors bind outside of the cleft. Moreover, the bivalent molecules that span two distinct regions of the kinase domain are type V inhibitors. Type-I–V inhibitors are all reversible. In contrast, compounds that bind covalently with the kinase active site are called type VI inhibitors (irreversible kinase inhibitors).
