SBIR Phase I: High-throughput platform for small molecule, in-cell targeting of undruggable proteins via their mRNAs

The broader impact of this Small Business Innovation Research (SBIR) Phase I project will be improvement of the health and welfare of Americans by providing an efficient and cost-effective approach for developing therapeutics for previously undruggable diseases, including hard to treat neurodegenerative diseases and highly aggressive cancers. Most diseases are targeted at the protein level using small molecule drugs, but only 600 proteins have ever been drugged directly. This collective human effort has left the majority of roughly 3,000 disease-related genes in humans undrugged and unable to be drugged using conventional pharmaceutical technology. Messenger RNAs (mRNAs) lie upstream of protein expression and, in principle, can be targeted to modulate protein function and treat disease. However, the physical and chemical properties of mRNAs present unique challenges not faced during protein-based drug discovery, and there has been little success in targeting mRNAs using small molecules. This project will address this unmet need by developing small molecule drugs against hard to treat and previously undruggable diseases by targeting their mRNAs directly. The proposed project will enable critical technical innovations needed to ensure the technical and commercial viability of a nascent drug discovery platform making it high-throughput and cost effective. The high throughput drug discovery platform to be developed creates an efficient path to screen for high-value drug assets and creates multiple pathways to new classes of therapeutics. The drug discovery platform currently has outstanding robustness and accuracy in defining interactions between small molecules and mRNAs in cells. However, the platform includes bespoke and hands-on steps and will remain a research-lab-only tool without critical innovations. The proposed project will improve the platform to be capable of fully automated ligand screening in cells using a library of complex small molecules optimized