UNC-Chapel Hill reaches milestone in development of Kinase Chemogenomic Set
The Structural Genomics Consortium at the University of North Carolina at Chapel Hill (SGC-UNC), in partnership with the DiscoverX Corporation, has reached the milestone halfway point in its development of the Kinase Chemogenomic Set, a potent group of inhibitors which allow deeper exploration of the human kinome, a family of enzymes critical to understanding human disease and developing new therapies.
By building this selective set of compounds and making it freely available, UNC-Chapel Hill and its partners are offering the scientific community a better understanding of the roles the kinome plays in human disease and the ability to collaborate on the discovery and advancement of new therapies.
The kinome, made up of enzymes called kinases, provides a tremendous opportunity for drug discovery. While more than 30 kinase inhibitors have been approved for the treatment of disease, the kinome has been largely unexplored until SGC-UNC, DiscoverX and other SGC partner companies embarked on this project.
“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 David Drewry, a research associate professor at the UNC Eshelman School of Pharmacy and SGC-UNC principal investigator 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 is available 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,” said Drewry. “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 and his fellow scientists aim to ensure the therapeutic potential of as many protein kinases as possible will be uncovered. The expansion of the KCGS, combined with its use in diverse disease-relevant phenotypic screens and the sharing of the resulting data in the public domain, is the best mechanism for reaching this goal.
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.
About the University of North Carolina at Chapel Hill
The University of North Carolina at Chapel Hill, the nation’s first public university, is a global higher education leader known for innovative teaching, research and public service. A member of the prestigious Association of American Universities, Carolina regularly ranks as the best value for academic quality in U.S. public higher education. Now in its third century, the University offers 77 bachelor’s, 111 master’s, 65 doctorate and seven professional degree programs through 14 schools and the College of Arts and Sciences. Every day, faculty, staff and students shape their teaching, research and public service to meet North Carolina’s most pressing needs in every region and all 100 counties. Carolina’s more than 318,000 alumni live in all 50 states and 157 countries. More than 167,000 live in North Carolina.
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 http://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.