System-based drug discovery within the human kinome

For well over a decade, significant effort has been devoted to the search for inhibitors of the human protein kinase family. This is increasingly translating into success in the clinic, with five new kinase inhibitor drugs approved since 2011. However, despite encouraging signs in other areas, success has been largely restricted to oncology.

This article reviews the prospects for kinase inhibitor drug discovery in oncology and other therapeutic areas. Major topics include the application of kinome profiling and lessons learned from kinase system-based research. With these fields nearing maturity, the validation of kinases as targets or their classification as liabilities is becoming increasingly pertinent. Other topics include a discussion of the properties required of good small molecule kinase probes.

The tractability of protein kinases to small molecule discovery through system-based research is excellent, and adequate selectivity can often be achieved. With advances in screening methodology now enabling compound profiling across most of the kinome, researchers involved in drug discovery must decide what inhibition profiles are desirable. However, this assessment must be made on the basis of incomplete understanding of the disease biology of most kinases, and as a result there is a significant risk that drugs entering clinical trials will lack efficacy. Because of this, as well as greater effort to determine which kinases are therapeutically relevant for particular diseases, opportunities for quality pre-candidate compounds developed for specific indications to find alternative uses should be maximised by early screening through panels of phenotypic assays.