The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. Two recent publications revisit the case for open science. Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over €5.4 million to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current (March 2022) Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda. SGC research activities take place in a coordinated network of university-affiliated laboratories – at Goethe University Frankfurt, Karolinska Institutet, McGill University, and the Universities of North Carolina at Chapel Hill and Toronto. The research activities are supported both by funds from the SGC Company as well as by grants secured by the scientists affiliated with the SGC programs. At each university, the scientific teams are led by a Chief Scientist, who are Stefan Knapp (Goethe University Frankfurt), Michael Sundstrom (Karolinska Institutet), Ted Fon (McGill University), Tim Willson (University of North Carolina at Chapel Hill), and Cheryl Arrowsmith (University of Toronto). The SGC currently comprises ~200 scientists.
Notable achievements
Chemical biology of human proteins Structural biology of human proteins – The SGC has so far contributed over 2000 protein structures of human proteins of potential relevance for drug discovery into the public domain since 2003. Structures that constitute complexes with synthetic small molecules is aided by a partnership with the Diamond synchrotron in Oxfordshire. The chemical probe program prioritizes (members of) protein families that are relatively understudied, or which may be currently relevant to human biology and drug discovery. These families include epigenetic signaling, solute transport, protein proteostasis, and protein phosphorylation. The protein family approach is supported by publicly available bioinformatics tools (ChromoHub, UbiHub), family-based protein production and biochemistry, crystallography and structure determination, biophysics, and cell biology (for example target engagement assays). The SGC has (so far) contributed ~120 chemical probes into the public domain over the past decade, and >25,000 samples of these probes have been distributed to the scientific community. The chemical probes conform to the now community-standard quality criteria created by the SGC and its collaborative network.
Epigenetic chemical probes that have generated clinical interest in their targets include PFI-1 and JQ1 for the BET family, UNC0642 for G9a/GLP, UNC1999 for EZH2/H1, LLY-283 and GSK591 for PRMT5, and OICR-9429 for WDR5. The WDR5 chemical probe was optimized (by a company external to the SGC) for clinical amenability and is the subject of investment from Celgene. Kinases have seen 50 drugs approved by the FDA for treatment of cancer, inflammation, and fibrosis. A review from two and a half years ago, a recent preprint, and peer-reviewed publication highlight low coverage of kinases both by peer-reviewed publications and 3D structures. In the last 4 years laboratories in Frankfurt, North Carolina and Oxford have developed chemical matter to help biologists study underrepresented kinases. In collaboration with pharmaceutical companies and academia, 15 chemical probes, and version 1.0 of 187 chemogenomic inhibitors (aka KCGS) for 215 kinases have been co-developed. Integral membrane proteins are permanently attached to the cell membrane. The family includes the solute carrier (SLC) proteins. The SLCs are largely unexplored therapeutically ~30% are considered 'orphaned' because their substrate specificity and biological function are unknown. In 2019 a public-private partnership comprising 13 partners, including the SGC, formed The RESOLUTE Consortium with funding from the IMI. RESOLUTE's goal is to encourage research on SLCs . The Target Enabling Package (TEP) is a collection reagents and knowledge on a protein target aimed to catalyze biochemical and chemical exploration, and characterization of proteins with genetic linkage to key disease areas. The SGC has opened target nominations to the public. The Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery (ULTRA-DD) program, funded by the European Commission's Innovative Medicines Initiative (IMI), aims to identify and validate under-explored targets in auto-immune and inflammatory disease models. Patient-derived cell lines are screened against chemical modulators (including chemical probes and chemogenomic compounds) with the intention of obtaining phenotypic read-outs in a disease relevant context. The Enabling and Unlocking biology in the Open (EUbOPEN) program, funded by the IMI, aims to assemble a chemogenomic library for ~1,000 proteins, discover ~100 high-quality, chemical probes, establish infrastructure to characterize these compounds, disseminate robust protocols for primary patient cell-based assays, while establishing the infrastructure to seed a global effort on addressing the entire druggable genome.
… excerpt ends here. Continue reading the full article.
