A resource for exploring the understudied human kinome for research and therapeutic opportunities

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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.</jats:p>

Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

“…See also Tables S2 and S7 and Data S1. ll (Moret et al, 2020). We detected 173 of these proteins in at least one experiment, and identified degraders for 40 proteins from this list ( Figure S1A; Table S4), validating them as pharmacologically related to protein kinases, and tractable TPD targets.…”

“…The human kinome contains approximately 55 pseudokinases, which are kinases that lack catalytic phospho-transfer activity but often have important scaffolding functions, making them potentially attractive targets for degraders (Moret et al, 2020). Out of 42 pseudokinases quantified, 10 were degradable by at least one compound in our set, including well characterized pseudokinases IRAK3 and TRIB3 ( Figure 1I; Table S4).…”

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

“…For reference, each kinase page provides an image from CORAL ( 22 ) that shows the kinase’s position in the broader kinase family phylogenetic tree (Figure 1A ). The 162 kinases under the purview of the DRGC span essentially all branches of the kinome tree, including several atypical kinases ( 1 , 24 ). A significant component of DRGC efforts involve development of mass spectrometry resources to support quantitative proteomics.…”

“…Protein kinases take a central position in many aspects of cellular signaling, with established roles in cellular growth, differentiation, migration and apoptosis. With well over 500 members ( 1 , 2 ), kinases also represent one of the largest gene families within humans ( 3 , 4 ). Likely arising from their central role in numerous functional processes, kinase dysfunction is similarly linked to pathologies including cancer, infectious disease and immune disorders.…”

“…This gap in knowledge is presumably due to highly related and potentially redundant gene function of kinase family members, redundancy in the signaling pathways they are part of, and tissue or developmental stage specificity. However, recent work is now demonstrating their potential importance in multiple disease contexts ( 1 , 6–8 ). The potential impact of better understanding these druggable and disease-relevant targets has thus led to the establishment of NIH’s Illuminating the Druggble Genome (IDG) Program ( 9 ).…”