The Druggable Transcriptome Project: From Chemical Probes to Precision Medicines

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• Matthew Disney - Scripps Research Institute
• Tuesday 01 April 2025, 14:30-15:30
• Department of Chemistry, Cambridge, Pfizer lecture theatre.

If you have a question about this talk, please contact Xani Thorman.

A scientific challenge is to understand biological pathways and to exploit the targets within them for therapeutic development. Coding and non-coding RNAs both directly cause disease, whether by mutation or aberrant expression. Akin to proteins, RNA structure often dictates its function in health or dysfunction in disease. RNA , however, is generally not considered a target for small molecule chemical probes and lead medicines, despite its immense potential. The focus of our research program is to uncover fundamental principles that govern the molecular recognition of RNA structures by small molecules to enable design of chemical probes that targeting disease relevant RNA structures to perturb and study their function.

I will describe using evolutionary principles to identify molecular recognition patterns between small molecules and RNA structures by studying the binding of RNA fold libraries to small molecule libraries. These interactions are computationally mined across the human transcriptome to define cellular RNAs with targetable structure. Such an approach has afforded bioactive interactions that have uncovered new biology, where the small molecules bind to functional structures within a target RNA . We have devised a strategy to imbue biologically silent RNA -small molecule interactions with cellular activity. Chimeras comprising an inactive small molecule and ribonuclease recruiter trigger targeted degradation of disease-causing RNAs. These degraders affect the biology of RNA in specific ways in cells and in mouse models of various diseases and can rationally reprogram protein-targeted medicines for RNA . Lastly, we have recently devised unbiased transcriptome wide approaches to define the RNA bound by small molecules is live cells. This allows us to study the RNA targets that are bound by small molecules, the selectivity of these interactions, and ways in which compounds of various types can modulate disease biology.

This talk is part of the Biological Chemistry Research Interest Group series.

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