Illuminating function of the understudied druggable kinome

• Published in: Drug discovery today 2024-03, Vol.29 (3), p.103881, Article 103881
• Main Authors: Gomez, Shawn M., Axtman, Alison D., Willson, Timothy M., Major, Michael B., Townsend, Reid R., Sorger, Peter K., Johnson, Gary L.
• Format: Article
• Language: English
• Subjects: chemical tools; dark kinase knowledgebase; human kinome; Humans; illuminating the druggable genome; miniTurbo; NanoBRET; Protein Kinases - metabolism; Proteins; Proteomics; SureQuant/PRM; understudied kinases
• ISSN: 1359-6446; 1878-5832; 1878-5832
• DOI: 10.1016/j.drudis.2024.103881

•There are more than 500 protein kinases in the human kinome of which 162 have been identified as understudied.•Assays were developed for quantitative measure of kinase protein expression and organization of kinase signaling networks.•Novel selective inhibitors of understudied kinases were used to determine function.•Computational analysis integrated experimental findings for illumination of the ‘dark’ kinome. The human kinome, with more than 500 proteins, is crucial for cell signaling and disease. Yet, about one-third of kinases lack in-depth study. The Data and Resource Generating Center for Understudied Kinases has developed multiple resources to address this challenge including creation of a heavy amino acid peptide library for parallel reaction monitoring and quantitation of protein kinase expression, use of understudied kinases tagged with a miniTurbo-biotin ligase to determine interaction networks by proximity-dependent protein biotinylation, NanoBRET probe development for screening chemical tool target specificity in live cells, characterization of small molecule chemical tools inhibiting understudied kinases, and computational tools for defining kinome architecture. These resources are available through the Dark Kinase Knowledgebase, supporting further research into these understudied protein kinases.