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

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Abstract
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. In this second part of a two-part review, we discuss the binding mode of inhibitors that target protein kinases in their inactive state. The scope of this review covers inhibitors for which crystal structures in complex with their respective kinases in the inactive state are available. 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.