The identification of drug-like small molecule medicines that directly bind to RNA and modulate its biological function will vastly increase our therapeutic target space, but targeting RNA comes with its own inherent challenges. The ensemble of conformations an RNA can adapt needs to be forefront when interpreting the results of biophysical and biochemical assays. We use a combination of repurposed tools to characterize the binding event and gain insight into how the ligands are interacting with the RNA target.

SMA is an inherited disease that leads to loss of motor function and ambulation, and a reduced life expectancy. We have been working to develop orally-administrated, systemically-distributed small molecules to increase levels of functional survival of motor neuron (SMN) protein. Herein, we describe the discovery risdiplam that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is completing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages of SMA.

Pre-mRNA splicing is emerging as a key control point in the expression of disease-modifying genes. Mutations causing alterations in splicing may result in diseases. Small molecules that affect pre-mRNA splicing have been identified and are being clinically developed. At PTC, we have developed a general approach to discover and develop drugs targeting splicing. Here we describe the application of this approach to spinal muscular atrophy, familial dysautonomia, and Huntington’s disease.

The potential of targeting mRNAs with small molecules has been unlocked, but the path that would lead to their discovery remains unclear. We are finding druggable motifs on any given mRNA and discovering small molecules targeting them using our ibVIS-SMD platform, which combines informatics with biophysical and cellular biology approaches. Here, we will describe how the ibVIS-SMD platform enables target identification, tailored screening of chemical libraries, hit validation, and structure-based lead optimization.

The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA. While some 80% of the human genome is transcribed into RNA, just ~3% of those transcripts code for protein sequences. Here we discuss our group’s efforts to target RNA and DNA with drug-like small molecules using a Small Molecule Microarray (SMM) screening platform and the molecular basis for these interactions.

Translation Control Therapeutics is the first platform for the discovery of small molecule drugs that selectively control mRNA translation. It uses patented technology that emits light pulses from ribosomes. This is followed by a rapid elucidation of the candidates' mechanism of action in a novel target space of untapped translation regulators. Our pipeline programs are in fibrosis, oncology, Huntington's disease, anti-virals and neurology, with most advanced candidates to enter clinical studies in 12-18 months.

Efforts targeting RNA with small molecules have been deterred by the inherent propensity of structured RNA molecules to adopt multiple conformations. The Baird Lab works to take direct advantage of RNA structural flexibility to discover small molecule inhibitors of RNA by simultaneously evaluating RNA structures and chemical screens. Our results demonstrate that targeting non-functional RNA structures is a challenging yet effective approach for therapeutic development.