The Structural Genomics Consortium at the University of North Carolina at Chapel Hill in partnership with the DiscoverX Corporation has reached the halfway point in developing a set of selective and potent inhibitors that will be made freely available to explore the human kinome, a family of more than 500 enzymes.
The kinome is made up of enzymes called kinases, and it provides a tremendous opportunity for drug discovery, said David Drewry, Ph.D., a research associate professor at the UNC Eshelman School of Pharmacy and a principal investigator of the SGC-UNC in the School. More than 30 kinase inhibitors have already been approved for the treatment of disease, but still the kinome remains largely unexplored. SGC-UNC, DiscoverX and other SGC partner companies are changing that.
By building a set of compounds that will allow investigation of this important family of proteins in its entirety, UNC Chapel Hill, DiscoverX and other partners are taking a critical step to better understand the roles the kinome plays in human disease. Freely releasing the Kinase Chemogenomic Set they are creating allows the scientific community to openly collaborate on the discovery and development of new therapies.
“Through our collaboration with DiscoverX, we screened a large set of compounds that we call Published Kinase Inhibitor Set 2, and these results allowed us to reach the halfway point in constructing the KCGS” said Drewry, who is leading the project to develop the Kinase Chemogenomic Set. “To mark this milestone and in keeping with our mission of open science, we are releasing these results into the public domain. We sincerely thank all of our co-author partners whose vision, generosity and hard work makes the construction of this set possible.”
A publication describing the team’s strategy and progress toward achieving a comprehensive KCGS appears online in the journal PLOS ONE. The manuscript also contains the results of screening each compound in PKIS2 against the DiscoverX panel of more than 400 kinase assays. PKIS2 is a collection of more than 500 kinase inhibitors donated by GSK, Pfizer and Takeda Pharmaceuticals that SGC-UNC makes available to the scientific community. The kinome wide annotation of inhibition profiles allows users of the set to interpret their results more readily.
“We have shown how well each of the PKIS2 compounds inhibits each of the kinases Discoverx screens,” Drewry said. “Researchers to whom we have given access to PKIS2 can use that information. They will know that compound X inhibits kinases A, B and C, but compound Z inhibits kinases D and E. With such a big data set people can easily find compounds of particular interest to them and know that the compounds are annotated with near full-kinome inhibition data.”
This collaborative project between industrial and academic scientists will continue to expand the KCGS with the goal of fully covering all human protein kinases, Drewry said. The scientists want to ensure that the therapeutic potential of as many protein kinases as possible will be uncovered, he said, and this expansion of the KCGS combined with its use in diverse disease-relevant phenotypic screens and sharing of the resulting data in the public domain is the best mechanism for doing so.
Authors and Funding
The work of the SGC-UNC is supported by a grant from the Eshelman Institute for Innovation.
The authors of the paper are David H Drewry, Carrow I Wells, David M Andrews, Richard Angell, Hassan Al-Ali, Alison D Axtman, Stephen J Capuzzi, Jonathan M Elkins, Peter Ettmayer, Mathias Frederiksen, Opher Gileadi, Nathanael Gray, Alice Hooper, Stefan Knapp, Stefan Laufer, Ulrich Luecking, Michael Michaelides, Susanne Muller, Eugene Muratov, R. Aldrin Denny, Kumar S Saikatendu, Daniel K Treiber, William J Zuercher and Timothy M Willson.
DiscoverX Corporation, headquartered in Fremont, California, designs, manufactures and sells biochemical and cell-based assays for the drug discovery and life science markets. Its portfolio of products and services are used to aid life science research and enable development of biologic and small molecule drugs by improving research productivity, effectiveness of screening, lead optimization and bioanalytical campaigns, as well as providing predictive tools that deliver physiologically relevant insights on drug molecules from early discovery through preclinical development.
About the Structural Genomics Consortium
In 2015 the UNC Eshelman School of Pharmacy became the first U.S. hub of the Structural Genomics Consortium, a precompetitive public-private partnership that accelerates research in human biology and drug discovery by making all of its research output freely available to the scientific community. The organization is building an open and collaborative network of scientists with active research facilities at six leading academic institutions across the globe: University of Toronto in Canada, Oxford University in England, UNICAMP in Brazil, Karolinska Institute in Sweden, University of Frankfurt in Germany UNC Chapel Hill in the U.S. SGC scientists collaborate with more than 300 researchers in academia and industry.
The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome Trust. For more information, visit www.thesgc.org. PKIS, a collection of more than 300 fully annotated kinase inhibitors donated by GSK, is currently available from the SGC-UNC by completing an on-line request.