Molecular glues are sticky molecules that could force disease-causing proteins to be dragged to the cell's waste disposal system and destroyed, but researchers have so far only found them by accident. This matters because conventional drugs work by blocking a protein's activity, which leaves around 85% of the human proteome—the collection of all proteins in the body—untouchable by current small-molecule strategies. Many of these "undruggable" targets drive serious diseases. Molecular glues offer a fundamentally different approach: instead of blocking a protein, they chemically tag it for degradation. But without understanding the rules that govern how these glues work, scientists cannot design them rationally or turn them into reliable therapies. If this project succeeds, it will create a "rule book" for discovering molecular glues on demand, rather than relying on luck. That could open up entirely new classes of drugs for diseases that currently have no treatment options. The research is a mix of fundamental science and applied development—it aims to uncover the basic biochemical principles of molecular glue action while simultaneously building industrial tools to exploit those principles. The ultimate beneficiaries would be patients with hard-to-treat conditions, though practical therapies remain years away.
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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.
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