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Details of Grant 

EPSRC Reference: EP/X025357/1
Title: Developing a rule book for rational discovery of molecular glues for intractable targets
Principal Investigator: Downward, Professor J
Other Investigators:
Strange, Ms A Kjaer, Dr S S Schreiber, Dr A A
Skehel, Dr JM Tate, Professor EW Scaffidi, Dr P
Howell, Dr M Walker, Dr P Enchev, Dr R R
Mercer, Dr P Ambrose, Miss K K
Researcher Co-Investigators:
Project Partners:
Department: Research
Organisation: The Francis Crick Institute
Scheme: Standard Research
Starts: 01 July 2023 Ends: 30 June 2028 Value (£): 4,132,670
EPSRC Research Topic Classifications:
Chemical Biology Drug Formulation & Delivery
Drug Formulation & Delivery Protein chemistry
EPSRC Industrial Sector Classifications:
Related Grants:
Panel History:
Panel DatePanel NameOutcome
15 Nov 2022 Prosperity Partnership Round 5 Full Proposal Announced
Summary on Grant Application Form
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.
Key Findings
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Potential use in non-academic contexts
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Date Materialised
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Organisation Website: https://www.crick.ac.uk