Signal transduction therapy with rationally designed kinase inhibitors

Signal transduction therapy has become one of the most important areas of drug research. Signaling disorders represent a major cause for the pathological states and many of the recently identified validated target molecules of drug research are signal transduction related macromolecules, mostly kinases. Rational drug design is aimed to achieve the selective inhibition of distinct pathologically relevant signaling enzymes or receptors. In the previous years, the concept of rational drug design has been expanded for a complex process including pathomechanism-based target selection, target validation, structural biology, molecular modeling, structure-activity relationships, pharmacophore-based compound selection and pharmacological optimization. The two main branches of the chemical rational drug design are structure-based design and ligand-based design. Some important examples for the application of 3D structure-based rational drug design in the development of clinically relevant kinase inhibitors are presented. The Nested Chemical Library (TM) (NCL) technology is a ligand-based design approach and relies on a knowledge-based approach, where focused libraries around published leads and selected cores are used to generate extended pharmacophore models (Prediction Oriented QSAR). NCL was designed on the platform of a diverse kinase inhibitor library, consisting of small molecule heterocycles, which are organized around 108 core structures. Some examples for testing the library on various targets and Prediction Oriented QSAR models will also be presented. The core elements of the kinase family-biased masterkey concept are the so-called privileged structures that emerge from a sophisticated molecular design and optimization process that encodes for a target family-wide structural commonality in ligand binding. The combination of a kinase family-wide imprinted commonality with additional structural fragments in the molecular periphery of a once established privileged structure allows to synthesize highly active and selective kinase inhibitors. In addition, several kinase inhibitors in preclinical or clinical development and application of 3D structure based rational drug design in the development of clinically relevant kinase inhibitors are reviewed.