Periodic Reporting for period 3 - EUbOPEN (EUbOPEN: Enabling and Unlocking biology in the OPEN)
Período documentado: 2022-05-01 hasta 2023-04-30
Almost twenty years after deciphering the human genome, our understanding of human disease is still far from complete. One of the most powerful and versatile tools to better understand biology and disease-relevant processes are well-characterised small chemical modulators of protein function. The Enabling and Unlocking Biology in the OPEN (EUbOPEN) project aims to develop high-quality chemical tool compounds, such as inhibitors or activators for 1,000 proteins (one third of the druggable proteins in the human body) and develop disease-relevant assays to test these tools. The project enables unencumbered access to these research tools, thereby empowering academia and industry alike to explore disease biology and unlock the discovery of new drug targets and treatments.
To study the function of a protein in any given cell type, scientists need small chemical tools that affect the target as specifically as possible, thereby avoiding unintended effects on other proteins. Therefore, there is an urgent need for selective and well-characterised chemical modulators for basic and applied research. Ideally, such tools would be available for every human protein. Moreover, these chemical modulators should be available to all researchers without restrictions on use, thus providing scientists with tools to better understand understudied proteins, and discover possible links to disease.
EUbOPEN generates potent, well-characterised, functional small-molecule modulators for novel target families by using new technologies and test them in well-characterised, disease-relevant human tissue assays in the areas of immunology, oncology and neuroscience. All project outputs, which include chemogenomic sets, chemical probes, protocols, assays and research data are being made openly available to the research community without restriction. With this set of chemical tools available, scientists will be poised to interrogate the latest findings emerging from big data approaches and human genetic studies, thus compressing time from gene discovery to target prioritisation, and ultimately reducing the time to bring innovative treatments and drugs to patients.
EUbOPEN has five high level objectives:
1. Assemble an open access chemogenomic library (a library of well-profiled compounds binding only to a small number of proteins) physically available compounds supported by meta-data;
2. Develop deeply-characterised chemical probes and ligands to specific protein family members;
3. Develop open access cell assay protocols and data from well-characterised human disease tissue to profile the chemical tools;
4. Establish infrastructure and resources that will live beyond the lifetime of this project;
5. Efficiently communicate and disseminate data and materials.
To study the function of a protein in any given cell type, scientists need small chemical tools that affect the target as specifically as possible, thereby avoiding unintended effects on other proteins. Therefore, there is an urgent need for selective and well-characterised chemical modulators for basic and applied research. Ideally, such tools would be available for every human protein. Moreover, these chemical modulators should be available to all researchers without restrictions on use, thus providing scientists with tools to better understand understudied proteins, and discover possible links to disease.
EUbOPEN generates potent, well-characterised, functional small-molecule modulators for novel target families by using new technologies and test them in well-characterised, disease-relevant human tissue assays in the areas of immunology, oncology and neuroscience. All project outputs, which include chemogenomic sets, chemical probes, protocols, assays and research data are being made openly available to the research community without restriction. With this set of chemical tools available, scientists will be poised to interrogate the latest findings emerging from big data approaches and human genetic studies, thus compressing time from gene discovery to target prioritisation, and ultimately reducing the time to bring innovative treatments and drugs to patients.
EUbOPEN has five high level objectives:
1. Assemble an open access chemogenomic library (a library of well-profiled compounds binding only to a small number of proteins) physically available compounds supported by meta-data;
2. Develop deeply-characterised chemical probes and ligands to specific protein family members;
3. Develop open access cell assay protocols and data from well-characterised human disease tissue to profile the chemical tools;
4. Establish infrastructure and resources that will live beyond the lifetime of this project;
5. Efficiently communicate and disseminate data and materials.
Open access chemogenomic library
In order to assemble an open access chemogenomic (CG) library, 1338 candidate CG compounds covering 569 targets have been acquired by EUbOPEN members and assessed for compound purity, structural integrity and cytotoxicity. Target family specific profiling assays have been set-up and to speed up characterisation of CG compounds and new technologies for compound profiling have been established.
Chemical probes and ligands
In total, 64 chemical tools (chemical probes/handles) from EUbOPEN, EFPIA partners and other partners collaborating with EUbOPEN have been approved by the independent scientific committee and made available to the research community. Together with experts in the field we have established criteria and reference ranges for degrader based chemical probes, which comprised recommendations for potency, selectivity and cellular activity, that will guide the characterisation and review mechanism of degrader based probes in the research community.
Chemical probe development has been supported and accelerated by parallel protein production, assay development and structural biology efforts as well as by the development of new technologies for hit identification. In the third year, more than 1,000 proteins of 450 unique targets have been purified to support hit identification and chemical probe generation. We established 160 in vitro assays and 109 cellular assays and a total of 120 CRISPR knockout cell lines have been made. More than 300 protein structures have been deposited in the PDB for public access together with detailed structural descriptions, including material and methods. Further hits have been identified using DNA encoded library screening, fragment screening (with Diamond XChem facility), in silico screening and via contributions from EFPIA partners. We also continued to focus on technology development and partnering with other academic and industrial efforts to maximise synergies and use of resources.
Open access cell assay protocols and data
EUbOPEN has focussed on developing open access cell assay protocols and data from well-characterised human disease tissue to profile the chemical tools in in four disease areas: inflammatory bowel disease, colorectal cancer, liver fibrosis and multiple sclerosis, in which patient-derived cell assays for compound screening have been developed and validated. Ten tissue assay protocols were established and made available to the research community together with screening data.
Infrastructure and dissamination of data and materials
In order to facilitate access to the results and outputs of EUbOPEN, we continued to improve and optimise the public-facing gateway. The gateway is an interactive tool which allows searching of data for different user communities, including chemists, biologists and informaticians in a compound or target centric fashion as well as browsing.EUbOPEN shared more than 6000 chemical tools with researchers in Europe, North America, Australia and Asia, thus contributing to studies that improve the understanding of fundamental human biology.
In order to assemble an open access chemogenomic (CG) library, 1338 candidate CG compounds covering 569 targets have been acquired by EUbOPEN members and assessed for compound purity, structural integrity and cytotoxicity. Target family specific profiling assays have been set-up and to speed up characterisation of CG compounds and new technologies for compound profiling have been established.
Chemical probes and ligands
In total, 64 chemical tools (chemical probes/handles) from EUbOPEN, EFPIA partners and other partners collaborating with EUbOPEN have been approved by the independent scientific committee and made available to the research community. Together with experts in the field we have established criteria and reference ranges for degrader based chemical probes, which comprised recommendations for potency, selectivity and cellular activity, that will guide the characterisation and review mechanism of degrader based probes in the research community.
Chemical probe development has been supported and accelerated by parallel protein production, assay development and structural biology efforts as well as by the development of new technologies for hit identification. In the third year, more than 1,000 proteins of 450 unique targets have been purified to support hit identification and chemical probe generation. We established 160 in vitro assays and 109 cellular assays and a total of 120 CRISPR knockout cell lines have been made. More than 300 protein structures have been deposited in the PDB for public access together with detailed structural descriptions, including material and methods. Further hits have been identified using DNA encoded library screening, fragment screening (with Diamond XChem facility), in silico screening and via contributions from EFPIA partners. We also continued to focus on technology development and partnering with other academic and industrial efforts to maximise synergies and use of resources.
Open access cell assay protocols and data
EUbOPEN has focussed on developing open access cell assay protocols and data from well-characterised human disease tissue to profile the chemical tools in in four disease areas: inflammatory bowel disease, colorectal cancer, liver fibrosis and multiple sclerosis, in which patient-derived cell assays for compound screening have been developed and validated. Ten tissue assay protocols were established and made available to the research community together with screening data.
Infrastructure and dissamination of data and materials
In order to facilitate access to the results and outputs of EUbOPEN, we continued to improve and optimise the public-facing gateway. The gateway is an interactive tool which allows searching of data for different user communities, including chemists, biologists and informaticians in a compound or target centric fashion as well as browsing.EUbOPEN shared more than 6000 chemical tools with researchers in Europe, North America, Australia and Asia, thus contributing to studies that improve the understanding of fundamental human biology.
The goal of EUbOPEN is to build a sustainable, open science public-private partnership and to provide infrastructure and standardised platforms that will nucleate and support a global effort targeting the entire druggable genome. As a step towards this global initiative, EUbOPEN contributes to the Target 2035 initiative, an international effort of biomedical scientists working in the public and private sector, with the aim of developing and applying new technologies to create chemogenomic libraries, chemical probes and biological probes for the entire human proteome by the year 2035. Like-minded consortia, such as the Illuminating the Druggable Genome initiative, Open Targets and EU-OPENSCREEN participate jointly in this initiative. Moreover, EUbOPEN teamed up with European initiatives such as FAIRplus to ensure our work enables a more open scientific culture, which will help to avoid duplication, and reduce both redundancy and wasting of resources. The unbiased systematic approach of EUbOPEN to enable new targets, will move research emphasis toward less studied proteins, and provide new insights and novel therapeutic opportunities. By sharing our science freely and in the open, and by continuously proving the merits of expanding the use of open science. EUbOPEN aims to become a landmark IMI2 project that exemplifies the remarkable benefits of open science and its long-lasting impact on the European research community and society.