Chemical genetic approaches to kinase drug discovery.

Chemical genetics is an important approach in biological research that utilizes small molecules to study protein function. In the context of kinase drug discovery, chemical genetics has broad applications in identifying and validating targets, demonstrating the druggability of a target and providing potential kinase inhibitor leads for further optimization. The successful application of this approach demands that the small-molecule kinase inhibitors used achieve a desired potency and selectivity. However, given the high number (> 518) and homology of kinases in the human genome, identifying potent and selective kinase inhibitors presents a major challenge. This article reviews recent advances in small-molecule kinase inhibitor design, with an emphasis on selectivity, and also discusses recent progress in the development of analog-sensitive kinase allele (ASKA)-based chemical genetics technology, which creates genetically engineered versions of protein kinases that are fully functional and can be selectively inhibited by a unique reference orthogonal inhibitor. Examples of how ASKA technology can be applied to kinase drug discovery is discussed.