Assessing Darkness of the Human Kinome from a Medicinal Chemistry Perspective

In drug discovery, human protein kinases (PKs) represent one of the major target classes, due to their central role in cellular signaling, implication in various diseases as a consequence of deregulated signaling, and their notable druggability. Individual PKs and their disease biology have been explored to different degrees, giving rise to heterogeneous functional knowledge and disease associations across the human kinome. The U.S. National Institutes of Health previously designated 162 understudied (“dark”) human PKs and lipid kinases, due to the lack of functional annotations and high-quality molecular probes for functional investigations. Given large volumes of available PK inhibitors (PKIs) and activity data, we have systematically analyzed the distribution of PKIs and associated data at different confidence levels across the human kinome and distinguished between chemically explored, underexplored, and unexplored PKs. The analysis provides a medicinal chemistry-centric view of PK exploration and further extends prior assessment of the dark kinome.