Exploring the understudied human kinome for research and therapeutic opportunities

The functions of protein kinases have been widely studied and many kinase inhibitors have been developed into FDA-approved therapeutics. A substantial fraction of the human kinome is nonetheless understudied. In this perspective, members of the NIH Understudied Kinome Consortium mine publicly available databases to assess the functionality of these understudied kinases as well as their potential to be therapeutic targets for drug discovery campaigns. We start with a re-analysis of the kinome as a whole and describe criteria for creating an inclusive set of 710 kinase domains as well as a curated set of 557 protein kinase like (PKL) domains. We define an understudied (‘dark’) kinome by quantifying the public knowledge on each kinase with a PKL domain using an automatic reading machine. We find a substantial number are essential in the Cancer Dependency Map and differentially expressed or mutated in disease databases such as The Cancer Genome Atlas. Based on this and other data, it seems likely that the dark kinome contains biologically important genes, a subset of which may be viable drug targets.