Identifying and evaluating understudied protein kinases using biological and chemical criteria

Abstract

Protein kinases (PKs) play a central role in cellular signaling. Uncontrolled signaling by deregulated PKs is implicated in a variety of diseases. As a consequence, PKs are among the most popular pharmaceutical targets. The preferred strategy for therapeutic intervention of medical conditions caused by deregulated PKs is the inhibition of their catalytic phosphorylation activity. Accordingly, small-molecular PK inhibitors (PKIs) have become a major drug class in oncology and prime candidates in other therapeutic areas. While cellular functions of many PKs and potential involvement in disease biology have been intensely investigated, others have received comparably little attention, leading to the identification of understudied 162 kinases representing the dark "dark kinome". Dark PKs have for the most part been categorized based on the absence of functional information and lack of reagents. Large-magnitude projects have been initiated to further explore and functionally characterize the dark kinome. In addition, different categories of PKs have also been defined based on their degree of chemical exploration in medicinal chemistry, representing complementary assessments of understudied PKs.

Fig. 1. Kinome distribution of understudied protein kinases. Understudied PKs are mapped on phylogenetic tree representations of the human kinome. At the top, the distribution of PKs is shown that were uniquely classified as either dark, un-/underexplored, or understudied by Berginski et al., Voßen et al., and Jiang et al., respectively. At the bottom, the distribution of PKs is shown that are shared by two or all three of these sets. Phylogenetic trees were drawn with CORAL (https://github.com/dphansti/CORAL).

Fig. 2. Dark Kinase Knowledgebase. The organization of the DKK with its integrated components is schematically illustrated. On the left, collected data and experimental techniques are shown and on the right additional tools provided by DKK. Abbreviations: GTEx: genotype-tissue expression; KCGS: kinase chemogenomic set; NanoBRET: Nano bioluminescence resonance energy transfer; PDBs: protein data bank files; PKIS1/2: published kinase inhibitor set 1/2; SureQuant/PRM: SureQuant/parallel reaction monitoring.

Fig. 3. Chemical versus functional exploration of protein kinases. For chemically unexplored, underexplored, and explored PKs, classification criteria are provided and the overlap between each category and dark PKs is specified.