Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition

Background: Protein kinases are essential Enzymes propagating cellular signal transduction processes and consequently emerged as central targets for drug discovery against a wide range of diseases with a strong historical focus on oncological disorders. Several high-resolution crystal structures of various ATP-competitive inhibitors in complex with their target protein kinases have been determined and represent a wealth of detailed information about binding modes, inhibition mechanisms, and associated structure- activity relationships of target-bound small molecules.

Objective: In this second part of a two-part review, we discuss the binding mode of inhibitors that target protein kinases in their inactive state.

Methods: The scope of this review covers inhibitors for which crystal structures in complex with their respective kinases in the inactive state are available.

Results: Structural parameters of both inhibitors and kinases contribute to the complexity of designing kinase inhibitors. Kinase inhibitors that target the inactive state of a kinase have become a novel rule in the design of highly active and selective compounds. The combination of high-resolution structures of ligand-enzyme complexes with especially detailed kinetic studies will in the long-term help to develop new low-molecular weight type II inhibitors.