RNAs play a paramount role in maintaining human health. Beyond their intermediary role as messenger RNA, RNAs perform diverse cellular functions, including regulating transcription, splicing, and translation. Called to action by discoveries connecting aberrant RNA biology with human diseases, targeting of RNAs with small molecules has arisen to the forefront of drug discovery. This talk will highlight technologies developed by the Garner laboratory for enabling RNA-targeted drug discovery.

Elsie Biotechnologies has developed an encoded platform to identify potent and safe oligonucleotide drugs. Our platform was used to discover RNase H-activating antisense oligonucleotides (ASOs) against a target. Oligonucleotides were optimized for knockdown and outperformed a clinical comparator ASO. First, encoded oligonucleotide pools were designed to tile the target, exploring every possible ASO sequence along the mRNA and pre-RNA transcript. ASO hits were identified and screened for in vitro knockdown activity. Subsequent rounds of platform selection optimized the molecule through screening ribose modifications and phosphorothioate (PS) stereochemistry. We are eager to expand the concept for optimization of other drug properties.

Despite significant advances, discovering RNA-targeted small molecules remains challenging. Here, I will present approaches combining multiple AIs, tailored for different drug discovery stages, with 3D structural analyses. Our AI-augmented iterative screening boosts SAR-tractable hit identification, while structural insights clarify binding modes and guide rational design, improving efficiency, selectivity, and ADMET properties. Supported by accumulated data and quantitative HTS, our approaches drive progess in RNA-targeted small molecule drug discovery.

Our mission at Arrakis is to solve very broadly the problem of how to drug RNA with small molecules. This presentation will provide an update on the platform we have built to achieve that mission and provide early data on specific mRNA targets.

Interdictors are small molecule context-dependent ribosome stallers that inhibit translation of disease-causing genes. We have developed interdictor molecules that potently inhibit the growth of short half-life oncogene-dependent cancers in vitro and demonstrate robust efficacy in multiple xenograft models in mice at a low oral, well-tolerated dose, as well as interdictors which reduce the synthesis of aggregation-prone neurotoxic proteins. A candidate in our lead program is undergoing IND-enabling characterization for clinical study in multiple MYC-driven tumor types.

snRNAs are required for the structure and function of the spliceosome. Here we report a potent and selective covalent ligand that targets TOE1, a 3’ RNA exonuclease, only when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1-Sm complex interactions and triggering the excessive trimming of snRNA 3’ termini in cells. Our findings may have therapeutic implications for splicing-related diseases.