Structural Genomics Consortium

A nonprofit consortium of bioscience researchers to openly share protein structure data
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 $5,4M Euros 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.

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. 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
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.

The Structure guided Drug Discovery Coalition (SDDC) comprises the Seattle Structural Genomics Center for Infectious Disease (SSGCID), the Midwest Center for Structural Genomics, the Center for Structural Genomics of Infectious Diseases (CSGID), and drug discovery teams from academia and industry has resulted in 7 early drug leads for tuberculosis (TB), malaria, and cryptosporidiosis. The SDDC receives funding from participating academic initiatives and the Bill & Melinda Gates Foundation. The University of North Carolina at Chapel Hill and the Eshelman Institute for Innovation, launched Rapidly Emerging Antiviral Drug Development Initiative (READDI™) and Viral Interruption to Medicines Initiative (VIMI™). REDDI™ is modelled after the non profit drug research and development Drugs for Neglected Diseases Initiative (DNDi). READDI™ and VIMI™ are non profit, open science initiatives that focus on developing therapeutics for all pandemic capable viruses.

Open science is a key operating principle. A Trust Agreement is signed before reagents are shared with researchers. These reagents include cDNA clones (Addgene), chemical probes, and 3D structures. Tools to promote open science include open lab notebooks. Parkinson’s disease, and Chordoma.

The for profit spin off companies M4K Pharma (Medicines for Kids), M4ND Pharma (Medicines for Neurological Diseases) and M4ID Pharma (Medicines for Infectious Diseases) do not file patents and practise open science. The M4 companies are wholly owned by a Canadian charity Agora Open Science Trust whose mandate is to share scientific knowledge and ensure affordable access to all medicines. M4K Pharma has the most advanced open drug discovery program

The new goal for structures was 650. The SGC focused considerable activities in the areas of ubiquitination, protein phosphorylation, small G proteins and epigenetics, and also initiated an effort in the structural biology of integral membrane proteins. In this phase, the SGC determined the structures of 665 human proteins from its Target List. With support from Wellcome and GSK, the SGC launched a program to develop freely available chemical probes to proteins involved in epigenetic signalling which at the time were under studied.

This phase built on the goals of previous phases but included well characterized antibodies to human proteins. The SGC initiated a concerted effort to develop disease relevant, cell based assays using (primary) cells or tissue from patients. This phase saw the launch of research activities at Goethe University in Frankfurt, at McGill University, and at the Universities of Campinas and North Carolina, and participation in ULTRADD and RESOLUTE The launch in November 2020 and monthly webinars have and continue to be free to attend. Supporting projects currently underway include the SGC’s epigenetics chemical probe program, the NIH’s Illuminating the Druggable Genome initiative for under explored kinases, GPCR’s and ion channels, IMI’s RESOLUTE project on human SLCs,