The Hargrove Lab leverages fundamental discoveries of the drivers of small molecule : RNA recognition to develop new strategies for RNA targeting. These methods account for differences in RNA chemical and conformational space to yield functional RNA-targeting small molecules and allow rational optimization without high-resolution structure.

The Kleiner lab develops chemical approaches to study RNA modifying enzymes and RNA-protein interactions. Here we will describe RNA-mediated activity-based protein profiling (RNABPP), a chemoproteomic strategy for profiling and inhibiting RNA modifying enzymes using mechanism-based modified nucleotide probes. We will also discuss TRIBE-ID, an RNA editing-based platform for studying RNA-protein interactions with temporal resolution.

The Abbasov laboratory exploits reactivity of lysines at RNA-protein interaction interfaces by leveraging activity-based proteomics and lysine-reactive natural products and small molecules. We developed activity-based acylome profiling, a chemoproteomic strategy that exploits elaborate acylating agents and lysine-centric probes for site-specific introduction and proteome-wide mapping of posttranslational lysine acylations in live cells. We identified paralog-selective chemical probes that acetylate lysines in interferon-stimulated antiviral RNA-binding proteins, generating proteoforms with obstructed RNA interactions.

Here, I will present our efforts that led to the identification of covalent ligands that alter RNA-protein complexes in human cells. The talk will focus on the discovery of novel chemotypes that stereo-selectively i) engage the RNA-binding protein NONO to decrease the expression of transcripts encoding the androgen receptor and its splice variants in prostate cancer cells, and ii) those that functionally remodel the spliceosome to perturb mRNA splicing.

We have developed new antibacterial small molecules by targeting an RNA hairpin within the ribosomal PTC, using a unique combination of NMR and computational chemistry. The optimization models utilized a dataset of small molecules, and their docking scores were essential in establishing design principles for new small molecules with improved bioactivity. We then synthesized these molecules, tested their ability to inhibit the ribosome, and demonstrated their binding mechanism to the RNA hairpin.

Unlike traditional AI that relies on existing knowledge, Anima's Lightning AI, a pioneering Visual Biology platform for drug discovery, generates new disease data by imaging cellular pathways through large-scale experimental biology. It trains neural networks on millions of visualizations, enabling them to visually recognize disease mechanisms, identify dysregulated pathways and novel, experimentally validated targets. It offers unbiased high-content, high- throughput screening of small molecules that revert disease signatures to their healthy state by modulating the mRNA biology of hard targets. 

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.

Rgenta Therapeutics is leveraging our proprietary, integrative RNA-targeting small molecule discovery platform to pioneer the development of first-in-class oral therapies. Rgenta is pursuing oncology and neurological disease targets, exemplified by the oncogenic transcription factor target c-MYB and the PMS1 gene. PMS1 is a key component of the DNA mismatch repair pathway, implicated in the pathological somatic trinucleotide repeat expansion observed in Huntington's Disease (HD) and other trinucleotide repeat expansion disorders.

Utilizing small molecules to modulate splicing is a successful therapeutic approach to regulate protein expression. EvrysdiTM (risdiplam) was recently approved for the treatment of Spinal Muscular Atrophy. PTC518 is in clinical development for Huntington’s disease. The learnings from the SMA and HD programs have helped PTC Therapeutics find other molecules for other diseases. Here, we discuss discovery, preclinical, and clinical development of small molecules that modulate pre-mRNA.

The PLAC8 gene is strongly ectopically expressed in pancreatic ductal adenocarcinoma (PDAC) and inhibition of PLAC8 expression significantly impairs cell proliferation and viability. Surprisingly, the functional entity mediating the cell-intrinsic pro-tumorigenic effects is not the PLAC8 protein, but instead the PLAC8 mRNA itself. Functionally, the PLAC8 mRNA, but not the protein, is centrally important for maintenance of genome integrity (and hence cell viability) via regulation of the MRN complex.

We present Cyclone, a novel acyclovir-controlled poison exon system designed for small molecule control of endogenous gene expression. By engineering the exon 7 hairpin structure from SMN1 to include an acyclovir-binding aptamer, we enable tunable, reversible, and dynamic regulation of both transgenes and endogenous genes. Cyclone offers a streamlined approach to controlling gene expression, harnessing naturally occurring RNA structures for efficient small molecule modulation.