The research tool: The Kinase Chemogenomic Set (KCGS)
There are approximately 518 kinases encoded within the genome but for over 150 of these, their substrate is unknown, leaving much of the kinome poorly annotated and little understood with respect to its role in human biology.
Dysregulation of kinases is a leading cause of oncogenesis and disease including immune, neurological, and infectious ailments. Disruption of kinase activity, be it upregulation or deactivation, can impact cell survival, proliferation or migration. However, 90% of the current research effort has been expended on only 20% of known kinases.
Understanding the remaining unstudied ‘dark’ kinases is essential to provide opportunities to discover new drug targets and diagnostic tools. Yet, there is still a lack of research tools/resources dedicated to these kinases.
The contributor
University of North Carolina at Chapel Hill (UNC) & Structural Genomics Consortium (SGC)
Developing a new tool kit
The Structural Genomics Consortium (SGC) is a non-profit organisation and home to scientists from medicinal chemistry, cell biology, and chemical biology. The SGC recognised the need to focus on the chemical biology of protein kinases. Operating out of the UNC Eshelman School of Pharmacy, these researchers have combined their skills to develop small molecule inhibitors aimed at ‘dark’ kinases to understand their structure, substrate, and function. This work resulted in the creation of the Kinase Chemogenomic Set (KCGS).
A core part of the SGC’s approach is its strong commitment to open science. Rather than keeping data or compounds behind closed doors, the team shares structures, profiling results, and insights openly with the global research community. This collaborative model encourages researchers to build on each other’s work, accelerates understanding of dark kinases, and ensures that the KCGS evolves through collective discovery and shared scientific progress.
Introducing the Kinase Chemogenomic Set (KCGS)
The Kinase Chemogenomic Set (KCGS) is the most diverse and comprehensively annotated publicly available collection of selective kinase inhibitors. Version 1.0 comprised 187 inhibitors with potent activity across 215 human kinases, contributed by eight pharmaceutical companies and leading academic laboratories. Version 2.0, which now replaces Version 1.0, expands the set with 108 additional inhibitors, bringing the total to 295 well‑profiled compounds.
KCGS enables researchers to identify medically important kinases and supports the development of high‑quality chemical probes, particularly for dark kinases—those that remain understudied or poorly characterised. Every inhibitor in the set has been cross‑screened across hundreds of kinases, and only compounds meeting stringent potency and selectivity criteria are included, a principle established in the original KCGS design.
Using these high‑quality inhibitors in phenotypic and mechanistic screens helps uncover the biology of unknown or dark kinases in both health and disease. Early characterisation of KCGS demonstrated strong utility for chemogenomic exploration of kinase signalling, revealing pathways and vulnerabilities that could lead to new therapeutic targets and serve as starting points for the development of future medicines.
KCGS impact
The KCGS set can be used in oncology and other life science research. A number of research projects have already made use of the KCGS to reduce the manual labour of sourcing and cross-screening each inhibitor across hundreds of kinases. Here are some of their results:
”greatly benefited from using KCGS in investigating cellular mechanisms of drug resistance in cancer by the application of chemogenomic libraries to discover novel kinase targets for pancreatic cancer treatment. KCGS has opened up new programs to study the viral-induced kinome and the discovery of small molecule inhibitors as potential anti-viral drugs
Lee Graves, UNC School of Medicine
Patrick Eyer, Institute of Integrative Biology
Using the KCGS has shaken up investigation into the phosphoproteome. Patrick Eyers from the Institute of Integrative Biology was studying how covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinae in cancer cells [3].
”KCGS has changed how we think about targeting unusual protein kinases, including pseudokinases and conformationally-restricted canonical kinases, with small molecules
Patrick Eyer, Institute of Integrative Biology
Daniel Ebner, University of Oxford
Using the KCGS, Daniel Ebner, has been able to identify kinase targets in neurodegeneration, cancer, wound healing, inflammation and cardiovascular disease [1], leading to several manuscripts already in publication. For example, thanks to KCGS, a novel synthetic lethal interaction between cyclin F loss and Chk1 inhibition was discovered, paving the way for patient selection in the clinical use of checkpoint inhibitors [2]
Discover how you can benefit from KCGS:
References
[1] Wells, CI. et al. 2021. Int J Mol Sci. 22(2):566. PMID: 33429995
[2] Burdova, K. et al. 2019. EMBO J. 38(20):e101443. PMID: 3142411
[3] Foulkes, D.M. et al. 2018. Sci Signal. 11 (549): eaat7951. PMID: 30254057.
