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. Improving the understanding of protein-kinase functions, downstream targets, signalling pathways and their role within disease can help direct the next step into creating new therapeutic and diagnostic tools. 

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 reagents/resources dedicated to these kinases. Currently, 90% of research effort has been expended on only 20% of known kinases. 

Developing a new toolkit

The Structural Genomics Consortium (SGC), a non-profit organisation, home to scientists from fields including medicinal chemistry, cell biology, and chemical biology, 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, with the aim of understanding their structure, substrate and function. This work resulted in the creation of the Kinase Chemogenomic Set. 

Introducing the Kinase Chemogenomic Set

The Kinase Chemogenomic Set (KCGS) is the most diverse and highly-annotated, publicly-available collection of kinase inhibitors. Version 1.0 of the set contains 187 kinase inhibitors with potent activity on 215 human kinases, sourced from eight pharma companies and leading academic laboratories. KCGS both helps scientists identify medically important kinases and allows for the synthesis of high-quality chemical probes for high priority dark kinases of therapeutic interest. Each inhibitor has been cross-screened across hundreds of kinases - only those meeting strict selectivity criteria are included in the set.

The use of these chemical inhibitors alongside screening assays will ultimately uncover the biology of these unknown/dark proteins in both health and disease. Preliminary characterization of the KCGS in phenotypic screens showed its potential for chemogenomic exploration of kinase signalling, which ultimately could lead to new targets for drug discovery and precursors to new medicines.

Current Impact

The KCGS set can be used in virtually any area of life science research, from virology to oncology to bacteriology. A number of research projects have already made use of the KCGS in their research to reduce the manual labour of sourcing and cross-screening each inhibitor across hundreds of kinases. Here are some of their results: 

Cristian Melander at University of Notre Dame has been working on bacterial behaviours. He said, "Access to the KCGS was key to our recent discovery that certain kinase inhibitors can be repurposed to modify bacterial behaviours… Opening a new chapter in our search for strategies to combat antibiotic-resistant infections."

Using the KCGS, Daniel Ebner, from the University of Oxford, has been able to identify kinase targets in neurodegeneration, cancer, wound healing, inflammation and cardiovascular disease, leading to several manuscripts already in publication and more in process. For example, KCGS demonstrated a novel synthetic lethal interaction between cyclin F loss and Chk1 inhibition, which ultimately should aid patient selection in the clinical use of checkpoint inhibitors. 

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) pseudokinase in cancer cells. He said "KCGS has changed how we think about targeting unusual protein kinases, including pseudokinases and conformationally-restricted canonical kinases, with small molecules."

Lee Graves, UNC school of medicine, described how his lab has ‘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.’