Developing a rule book for rational discovery of molecular glues for intractable targets
Lead Research Organisation:
The Francis Crick Institute
Department Name: Research
Abstract
The UK has established world class capabilities in genomics and bioinformatics thanks to unique initiatives including Genomics England and the Wellcome Sanger Institute-led Open Targets platform and Cancer Dependency Map. These activities anchor multinational pharmaceutical companies in the UK, and underpin a highly successful and competitive biotech sector which raised a record £3 billion in new investment in 2021. While these UK-led programmes have contributed much to the understanding of the role the key players in driving many diseases, 85% of the proteomeis currently accessible through current small molecule strategies; referred to as the "undruggable" proteome.
Conventional pharmacology approaches rely on small organic molecules which alter the activity of a given receptor or enzyme. Promising alternatives to these approaches are offered through molecules which reduce the abundance of aberrant target proteins, chemically tagging them and redirecting them for degradation through the cell's natural waste disposal system. In particular, a class of compounds, known as molecular glues, have recently been shown to enhance degradation of previously undruggable targets, potentially enhancing the therapeutically actionable space. Despite significant potential for impact, molecular glue discovery has so far been serendipitous, with a poor understanding of mechanism of action and the rules which govern their pharmacology, significantly reducing translational development in this area.
Through this Prosperity Partnership, we propose developing an end-to-end approach to develop an understanding of the pre-requisites of molecular glues, using key biological pathways studied by Crick Researchers as the testing ground. Through this approach we will develop novel industrially relevant technology in areas hitherto untouched by conventional therapeutics, enhancing biological understanding and ultimately benefitting patients with difficult to treat diseases.
Conventional pharmacology approaches rely on small organic molecules which alter the activity of a given receptor or enzyme. Promising alternatives to these approaches are offered through molecules which reduce the abundance of aberrant target proteins, chemically tagging them and redirecting them for degradation through the cell's natural waste disposal system. In particular, a class of compounds, known as molecular glues, have recently been shown to enhance degradation of previously undruggable targets, potentially enhancing the therapeutically actionable space. Despite significant potential for impact, molecular glue discovery has so far been serendipitous, with a poor understanding of mechanism of action and the rules which govern their pharmacology, significantly reducing translational development in this area.
Through this Prosperity Partnership, we propose developing an end-to-end approach to develop an understanding of the pre-requisites of molecular glues, using key biological pathways studied by Crick Researchers as the testing ground. Through this approach we will develop novel industrially relevant technology in areas hitherto untouched by conventional therapeutics, enhancing biological understanding and ultimately benefitting patients with difficult to treat diseases.
| Description | Early Career Researcher Symposium and Networking Joint Event, for the MRC Laboratory of Molecular Biology and The Francis Crick Institute collaborations with AstraZeneca |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | The symposium took place at The AstraZeneca Discovery Centre, Cambridge Biomedical Campus, Cambridge and hybrid attendance were available. interest Background: AstraZeneca sponsor a number of different collaboration programmes with two research institutes: The Francis Crick Institute and the The Laboratory of Molecular Biology (LMB), supporting discovery biology research and early translational projects. In addition, for this year the symposium also included the team from the Prosperity Partnership with the Crick and Imperial College London. Aims and Objectives: This is an in-person community building event for the early career researchers engaged in our three different collaboration programmes with AstraZeneca. The event contained scientific talks from group leaders and postdocs, followed by a social and networking event. |
| Year(s) Of Engagement Activity | 2024 |
| Description | Medicine at the Crick: New Frontiers in Drug Discovery Symposia |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | The 15th edition of Medicine at the Crick was hosted by Anne Schreiber (The Francis Crick Institute) and Radoslav Enchev (The Francis Crick Institute) on behalf of the AstraZeneca-Crick-Imperial Prosperity Partnership. Symposium description: Many human diseases are caused by a deregulation of cellular components. Most traditional drugs target disease-causing proteins aiming to inhibit their activity by binding to their active site. However, specificity is often challenging, and only a small subset of these harmful proteins can be targeted in this way. A promising new class of drugs, known as induced proximity therapeutics, addresses these shortcomings by bringing two proteins close together to trigger functional changes or degradation, thereby suppressing the disease-causing effect. This shift from blocking to actively changing a protein of interest by engaging other cellular factors represents a groundbreaking new approach in drug development, expanding into previously undruggable targets to treat many diseases including cancer, inflammation, and neurodegeneration. The symposium contained national and international speakers: Speakers and panellists include: Prof Ray Deshaies (Amgen), Dr Miklos Bekes (Arvinas), Dr Leon Murphy (Casma Therapeutics), Prof Zoran Rankovic (Institute of Cancer Research), Prof Michael Bronstein (University of Oxford), Prof Charlotte Deane (EPSRC and the University of Oxford), Dr Cristina Mayor-Ruiz (IRB Barcelona), Prof Christina Woo (Harvard University), Prof Sagar Lonial (Winship Cancer Institute of Emory University), Prof Ivan Dikic (Goethe University Frankfurt) Lectures were followed by a Q&A panel discussion and a networking reception for in-person attendees. A more detailed programme will be made available soon. The speaker programme is in-part supported by a UKRI Prosperity Partnership Award involving AZ, the Crick and Imperial College: Developing a rule book for rational discovery of molecular glues for intractable targets. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.crick.ac.uk/whats-on/medicine-at-the-crick-new-frontiers-in-drug-discovery |