Small-molecule inhibitors binding to protein kinases. Part I: exceptions from the traditional pharmacophore approach of type I inhibition

BACKGROUND: Protein kinases are essential enzymes propagating cellular signal transduction processes and consequently have emerged as central targets for drug discovery against a wide range of diseases with a strong historical focus on oncological disorders. A large number of high-resolution crystal structures of various ATP-competitive inhibitors in complex with their target protein kinases have been determined and present a wealth of detailed information about binding modes, inhibition mechanisms and associated structure-activity relationships of target-bound small molecules. OBJECTIVE: In this first part of a two-part review, exceptions to the type I binding mode of kinase inhibitors that follow the traditional pharmacophore model are discussed, highlighting unexpected structural features. METHODS: The scope of this review covers published crystal structures of protein kinases in complex with various ligands. RESULTS: Structural parameters of both inhibitors and kinases contribute to the complexity of designing kinase inhibitors. The continued study of high-resolution structures of ligand-enzyme complexes in combination with a more dynamic understanding of accessible conformational states of the target proteins, supported by detailed kinetic studies, will in the long-term help in developing new low-molecular weight kinase inhibitors.