Kinase Chemogenomics

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The human genome contains hundreds of dark kinases that are poorly characterized and for which little is known about their role in human disease. SGC-UNC scientists have championed a method of studying the biology of dark kinases, called chemogenomics. The approach utilizes ATP-competitive kinase inhibitors that show cross-activity on multiple kinases. The most useful ‘narrow-spectrum’ inhibitors have activity on 2 to 10 kinases. SGC-UNC scientists have assembled a large matrix of these narrow-spectrum kinase inhibitors into a chemogenomic set to probe the cell biology of the dark kinases.

Our first chemogenomic set contained 367 small molecule kinase inhibitors that were previously published by chemists at GSK. The set was named the Published Kinase Inhibitor Set (PKIS). It was carefully selected to maximize chemical and biological diversity of the inhibitors. Broad profiling at NanoSyn and the SGC Oxford showed that PKIS had activity across over 150 human kinases. PKIS was made available to the scientific community as a resource to study kinase biology and to uncover potential new targets for drug discovery. A growing number of peer-reviewed papers have been published that report on the use of PKIS in the biomedical research.

Building on this success, a second chemogenomics set of kinase inhibitors from GSK, Takeda, and Pfizer was assembled as PKIS2. This set contained 645 inhibitors and included many additional chemotypes that were not represented in the original set. PKIS2 was profiled using the DiscoverX KINOMEscan affinity capture technology and shown to index 250 human kinases. PKIS2 was also made widely available to the scientific community. Feedback from scientists who received PKIS or PKIS2 was collected in a survey that the showed the value of these chemogenomic sets as tools to uncover new kinase biology.

Detailed analysis of the activity profiles of PKIS and PKIS2 has allowed the design of a new Kinase Chemogenomic Set (KCGSv2.0) with improved coverage of the human kinome. Importantly, KCGS contains only potent narrow spectrum kinase inhibitors thereby facilitating the annotation of phenotypic data and hypothesis generation. KCGSv2.0 is now available from CancerTools.org.