Reference Systems for Kinase Drug Discovery: Chemical Genetic Approaches to Cell-Based Assays

Protein kinases play key roles in a number of diseases, including cancer, inflammation, and diabetes. Disregulation of kinase-based signal transduction networks results in aberrant cell differentiation, activation, proliferation, and invasion. The growing importance of kinases as a major class of drug targets across multiple large clinical indications, together with the large number of kinases in the genome (∼518), has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors with good drug-like properties. In this review, we describe methods used for developing cell-based assays for kinase inhibitors, discuss advantages and disadvantages of each approach, and describe new chemical genetic methods as reference systems for establishing cell-based assays and their use for functional selectivity profiling of kinase inhibitors.