Developing Drug-like Small Molecules that Target Toxic Repeat RNAs to Alleviate Myotonic Dystrophy Type 1-derived Mis-Splicing

Project Summary Abstract Nymirum will utilize its technology platform to identify and optimize a drug-like, orally available small molecule that binds toxic CUG repeat RNAs to rescue myotonic dystrophy type 1 (DM1) derived mis-splicing and treat the disease. DM1 is a rare genetic disorder that leads to progressive muscle degeneration, cardiovascular disease, severe cognitive disabilities, insulin resistance, and a host of other symptoms. There is no cure for DM1, and the only treatments are palliative. The cause of DM1 is an abnormal CTG trinucleotide repeat expansion (andgt;34 repeats) in the 3′-UTR of DMPK that are transcribed into toxic CUG RNA repeats that accumulate in the nucleus of cells. Toxic CUG repeats sequester Muscleblind Like Splicing Regulator 1 (MBNL1), which is needed for normal splicing of hundreds of key neuromuscular related genes. Studies have shown that small molecules that bind CUG repeats can prevent MBNL1 sequestration and rescue nominal splicing in cells and animal models. However, these small molecules are bulky, very polar, and non-drug-like and therefore suffer from delivery and toxicity issues. Therefore the need remains to identify and optimize drug-like, orally available small molecules that bind CUG repeats and rescue DM1-derived mis-splicing in cells. Preliminary data highlights that the Nymirum platform has identified two classes of drug-like small molecules that can bind CUG repeats and can rescue DM1-derived mis-splicing in HeLa cells. This proposal seeks to go wider and deeper in order to identify and optimize more potent compounds. In Phase I, andgt;2 billion compounds will be rapidly and accurately screened to identify additional classes of chemically diverse drug-like small molecule CUG binders. Those hits will then be optimized at the atomic level using the dynamic CUG structure to guide targeted medicinal chemistry to increase their potency and efficacy in HeLa cells. Phase II will carry out lead-generation in earnest on the hits identified in Phase I. Ultimately, this proposal will develop an orally available small molecule therapeutic to treat DM1.Project Narrative Nymirum is leveraging its platform to develop an orally available small molecule therapeutic that rescues myotonic dystrophy type 1 derived mis-splicing by binding toxic CUG RNA repeats and preventing them from sequestering a key splicing regulator (MBNL1).