Structural Genomics Consortium

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^1,2. As a core principle, the SGC places all its research output into the public domain without restriction and never files for patents, making the SGC one of the leading proponents of open science^3-13.

Governance

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 (August 2020) Members comprise AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, MSD (Merck, Sharpe and Dohme), Pfizer, Takeda, and Wellcome Trust.

SGC research activities take place in a coordinated network of university-affiliated laboratories – at Goethe University Frankfurt, Karolinska Institutet, McGill University 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.

Major Scientific Programs at the SGC

Structural biology of human proteins – The SGC has contributed over 2200 structures of human proteins of potential relevance for drug discovery into the public domain since 2003, and this effort continues.  An increasing number of structures constitute complexes with synthetic small molecules, an effort that is aided by a strategic partnership with the Diamond synchrotron in Oxfordshire¹⁴.  

Chemical biology of human proteins

The SGC chemical probe program is focused on members of protein families in areas of science of relevance for human biology and drug discovery, and include epigenetic signaling^15,16, solute transport^17,18, protein proteostasis^19-23, and protein phosphorylation^11,24,25. Scientific strengths include bioinformatics (ChromoHub, UbiHub) for target identification and selectivity assays, protein production and biochemistry, crystallography and structure determination, biophysics, and cell biology (including target engagement assays). The SGC has contributed ~100 chemical probes ^9,26,27 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^9,28-32. Notable chemical probes include PFI-1³³ and JQ1³⁴ for the BET family, UNC0642³⁵ for G9a/GLP, UNC1999³⁶ for EZH2/H1, and OICR-9429³⁷ for WDR5.

Seeding drug discovery

Through open science the SGC catalyzes drug discovery programs with a focus on the under-studied proteome. JQ1³⁴, was used to validate BET bromodomains as tractable drug targets in cancer. There have been 35 clinical trials on bromodomain containing proteins (including 20 on the BET family), and additional bromodomain chemical probes are enabling research on over 20 targets²⁶. Most recently, a drug discovery program in blood cancers was initiated based on data obtained using the open access chemical probe OICR-9429³⁷ that was co-developed by OICR and SGC. This probe linked WDR5 (a component of the MLL1 complex) to tumor growth suppression in leukemia. The drug discovery program resulted in a lead compound that ultimately attracted a strategic collaboration worth $40M USD. Currently (08/20) there are ~15 clinical trials on 5 (non-bromodomain) epigenetic targets each of which the SGC has developed chemical probes.

The Target Enabling Package (TEP) programme is built upon the recognition that genetic data is proving to be a powerful tool for target validation. TEPs provide a critical mass of reagents and knowledge on a protein target to allow rapid biochemical and chemical exploration and characterisation of proteins with genetic linkage to key disease areas. This dataset aims to catalyse new biology and disease understanding to target/ drug discovery. The SGC has opened target nominations to the public.

To provide relevant data for target validation the SGC started the Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery (ULTRA-DD) program with funding from the European Commission’s Innovative Medicines Initiative (IMI). The goal is to identify and validate under-explored novel targets in auto-immune and inflammatory diseases creating and profiling target-directed chemical and antibody probes in the highest quality patient-cell derived assays, providing biomarker and phenotypic read-outs in a more disease relevant context³⁸.

In the realm of non-human proteins, the SGC led Structure-guided Drug Discovery Coalition (SDDC) comprising the Seattle Structural Genomics Center for Infectious Disease (SSGCID), the Midwest Center for Structural Genomics, the Center for Structural Genomics of Infectious Diseases (CSGID), academic researchers in North America and Europe, and drug discovery teams from academia and industry has so far 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.

More recently, the SGC, the University of North Carolina at Chapel Hill and the Eshelman Institute for Innovation, announced the launch of a global organization Rapidly Emerging Antiviral Drug Development Initiative (READDI™) and Canada-based Viral Interruption to Medicines Initiative (VIMI™). REDDI™ is modelled after a successful model for non-profit drug research and development Drugs for Neglected Diseases Initiative (DNDi). READDI™ and VIMI™ non-profit, open science initiatives will focus on developing therapeutics for all viruses that have pandemic potential.

Open Science

Since 2004, open science has been at the core of the SGC, and this was codified in the SGC Open Science Principles, which were developed by Edwards and Richard Gold, of McGill University. The principles^3-5,39, supported by the SGC host institutions, state that no SGC scientist will agree to file for a patent on any of their research activities, including medicinal chemistry. Freely available research reagents and technologies discovered and developed by the SGC, including cDNA clones (Addgene), chemical probes, 3D structures, experimental protocols, are being used by thousands of laboratories around the world.

SGC scientists have been profiled extensively for their contributions to open science and have been pioneering even more rapid dissemination of their science using Open Lab Notebooks⁸. This is particularly impactive to rare diseases, patient groups and disease foundations. For example diffuse intrinsic pontine glioma (DIPG), Fibrodysplasia ossificans progressiva, Huntington’s disease^7,40, Parkinson’s disease, and Chordoma.

Open Drug Discovery

For 15 years, the SGC has maintained that the early stages of drug discovery, from new therapeutic hypothesis to proof-of-concept in patients should be for public good and should take place in the open^3-8,10. The concept is being reduced to practice within a series of spin-off “no patent, open science” pharma companies⁶. These for-profit companies include M4K Pharma (Medicines for Kids), M4ND Pharma (Medicines for Neurological Diseases) and M4ID Pharma (Medicines for Infectious Diseases).

All the M4 companies are wholly owned by a Canadian charity, whose mandate is to share scientific knowledge and ensure affordable access to all medicines. M4K Pharma has the most advanced open drug discovery program. Supported with funding from the Ontario Institute for Cancer Research, the Brain Tumour Charity, Charles River Laboratories and Reaction Biology, and with contributions from scientists at the Universities of McGill, North Carolina, Oxford, Pennsylvania, and Toronto and in the Sant Joan de Déu hospital, the University Health Network hospitals, the Hospital for Sick Children, and The Institute of Cancer Research, M4K Pharma is developing a selective inhibitor of ALK2¹³ for DIPG, a uniformly fatal pediatric brain tumour.

Scientific Themes

Kinases have been the focus of many drug discovery programs and 50 drugs have been approved by the FDA for treatment of cancer, inflammation, and fibrosis⁴¹. But based on the literature only ~20% of the kinome has been studied. To expand the druggable kinome²⁴ the laboratories in Frankfurt, North Carolina and Oxford have so far contributed to one third of the deposited structures of kinases, and in collaboration with pharmaceutical companies and academia co-developed 11 chemical probes (and matching negative controls), and version 1.0 of 187 well-characterized chemogenomic inhibitors (aka KCGS) for 215 targets^11,25.

Epigenetic proteins regulate chromatin condensation or participate in DNA-templated processes and have been classified as “writers,” “erasers,” and “readers”¹⁵. Laboratories in Oxford and Toronto have (in the last 10 years) co-developed with pharmaceutical and academic partners 57 chemical probes and 44 negative controls.

Ubiquitin signaling proteins can be similarly grouped into “writers,” “erasers,” and “readers”. By August 2015 the SGC had already solved (and deposited) the structures of over 65 protein domains involved in ubiquitin signaling^42-44. Building on this, the SGC has been ramping up its activities in this protein family over the last 5 years^20-23,45.

Integral membrane proteins which are permanently attached to the cell membrane include the solute carrier (SLC) proteins. The SLCs are largely unexplored therapeutically and in fact as many as 30% of all SLCs 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 The RESOLUTE Consortium¹⁸ with funding from the IMI. RESOLUTE’s strategic goal is to foster appreciation and intensity of research on SLCs to establish the family as a tractable class for R&D.   

History

The Concept

In 2000, a group of companies and Wellcome conceptualized forming a Structural Genomics Consortium (SGC) to focus on determining the three-dimensional structures of human proteins¹. The aim of the consortium was to place all structural information and supporting reagents into the public domain without restriction. The effort was designed to complement the other structural genomics programs in the world, which at the time focused largely on microbial proteins and aimed either identify new protein folds, or to achieve broad structural coverage of an organism (https://en.wikipedia.org/wiki/Structural_genomics).

Phase I (2004-2007)

In July 2004, the SGC scientific program was launched, with activities at the Universities of Oxford and Toronto, and with a goal to contribute >350 human protein structures into the public domain by mid-2007. To be counted toward these goals, the proteins had to derive from a pre-defined list and the protein structures were required to meet pre-defined quality criteria. The quality of protein structures was and continues to be adjudicated by a committee of independent academic scientists. Michael Morgan was the Chair of the SGC Board, and the scientific activities were led by Cheryl Arrowsmith (Toronto) and Michael Sundstrom (Oxford). In mid 2005 VINNOVA, Knut and Alice Wallenberg Foundation and The Foundation for Strategic Research (SSF) established the Swedish research node of the SGC. Experimental activities were launched at the Karolinska Institutet in Stockholm, led by Pär Nordlund and Johan Weigelt. Together, the three SGC laboratories contributed 392 human protein structures into the public domain by July 2007. A pilot program in the structural biology of proteins in the malaria parasite was also initiated⁴⁶.

Phase II (2007-2011)

The new SGC mandate was to determine the structures of 650 proteins by mid 2011.  In this phase 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.

In 2009, with support from Wellcome and GSK, the SGC launched a program to develop freely-available chemical probes to proteins involved in epigenetic signalling. This effort was predicated on the notion that there were many human proteins that received too little attention by the research community and the observation that research on previously lesser-studied human proteins increased upon the availability of a chemical probe^2,4. To ensure that the chemical probes were of the highest quality, each was subject to two levels of review prior to their dissemination to the public. The first level was internal, through a Joint Management Committee comprising representatives from each member organization. The second was provided by a group of independent experts selected from academia.  This level of oversight was key to developing reagents of sufficient quality to support reproducible research^47-49, and led to the creation of the Chemical Probes Portal, which is a community-driven effort to provide expert insight into the quality and use of published chemical probes.

The SGC Memberships expanded to include Merck, Sharpe and Dohme, and Novartis. Wayne Hendrickson served as the Chair of the SGC Board.

Phase III (2011-2015)

The SGC mandate diversified to include goals of protein structures (200, including 5 structure of human integral membrane proteins) and chemical probes (30). Many of the chemical probes’ programs were undertaken in partnership with scientists in the pharmaceutical companies, which made the commitment to contribute the collaborative chemical probe into the public domain, without restriction.

In Phase III, the SGC, along with the SSGCID (https://www.ssgcid.org/) and the CSGID (https://csgid.org/), also launched the Structure-guided Drug Discovery Coalition. The SDDC, which continues to be funded by the Bill and Melinda Gates Foundation and led by Chris Walpole, was formed to develop early drug leads for malaria and tuberculosis. To date, the SDDC and its partners have delivered 7 early-leads into the TB, malaria, and cryptosporidiosis drug discovery pipelines.

The SGC Memberships expanded to include AbbVie, Bayer AG, Boehringer Ingelheim, Eli Lilly and Janssen.  Markus Gruetter became the Chair of the SGC Board. Merck, Sharpe and Dohme left the consortium, as did the Canadian Institutes for Health Research.

Phase IV (2015-2020)

This phase included goals to generate new protein structures, new chemical probes and renewable and well-characterized antibodies to human proteins. Importantly 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^17,18 within IMI.

The SGC Memberships expanded to include Merck KGaA and the Eshelman Institute for Innovation.  Merck, Sharpe and Dohme re-joined while GSK and Eli Lilly left the SGC.  Tetsuyuki Maruyama became the Chair of the Board.  

The Future - Target 2035

Target 2035 is an open science initiative with the goal of creating chemical^11,20,26,27 and/or biological^12,50 tools for the entire proteome by 2035⁵¹. Seed projects currently underway include the SGC’s epigenetics chemical probe program^52,53, the NIH’s Illuminating the Druggable Genome initiative for under-explored kinases, GPCR’s and ion channels^54-56, and IMI’s RESOLUTE project on human SLCs^17,18. These teams are linked to SGC’s global collaborative network^{2,9,29,38,49,50} and Target 2035 is intended to draw from these experiences to bring the ‘dark genome’ into the light thus creating the opportunity to develop new therapeutics.

External links

• Partner List
• Global SGC website
• SGC Campinas
• SGC UNC
• SGC Frankfurt
• SGC Karolinska
• SGC Toronto
• SGC Oxford
• Chemical probe resources: Chemical Probes Portal, Probe Miner, SGC Chemical Probes, SGC Donated Chemical Probes Program
• Chemogenomics: Kinase Chemogenomic Set v1.0