The Dark Kinase Knowledgebase: an online compendium of knowledge and experimental results of understudied kinases

Abstract

Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH's Illuminating the Druggable Genome (IDG) Program, the DKK is focused on data and knowledge generation for 162 poorly studied or 'dark' kinases. Types of data provided through the DKK include parallel reaction monitoring (PRM) peptides for quantitative proteomics, protein interactions, NanoBRET reagents, and kinase-specific compounds. Higher-level data is similarly being generated and consolidated such as tissue gene expression profiles and, longer-term, functional relationships derived through perturbation studies. Associated web tools that help investigators interrogate both internal and external data are also provided through the site. As an evolving resource, the DKK seeks to continually support and enhance knowledge on these potentially high-impact druggable targets.

Figure 1.

Several types of data related to dark kinases are displayed on the individual kinase pages. (A) Kinase tree showing the location of PKMYT1 in the canonical kinase phylogenetic tree (3) produced using CORAL (22). (B) Calibration curve related to a PRM peptide related to PKMYT1. (C) Interactive visualization of APMS physical interaction network building using Cytoscape.js (23) for PKMYT1. (D) Display of the tool compound for kinase STK17B.

Figure 2.

Sample screenshot from the Dark Kinase Expression browser (http://expression.darkkinome.org) with MKNK2 selected. Individual sections of the page are highlighted with colored boxes and associated labels. Along the top edge is a tabbed interface for selecting methods of browsing (either by kinase or organ system) and the type of data (GTex Consortium or Human Protein Atlas). The colors in the anatogram figures only mark the organs expressing the selected kinase.

Figure 3.

Several tools affiliated with the Dark Kinase Knowledgebase. (A) CORAL: the kinase tree visualization tool. (B) The Clinical Kinase Index, which focuses on the kinase’s role in cancer. (C) The IDG Reactome portal provides a window into the Reactome database centered around understudied genes. (D) The Small Molecule Suite toolkit for selection of kinase inhibitors