Myotonic dystrophy 1 (DM1) is the leading form of adult muscular dystrophy resulting in progressive neuromuscular effects. The disease affects 1 in 6000 people. Nymirum is interested in identifying a small molecule that can be used to slow or eliminate the progression of DM1. The cause of DM1 is the expansion of a CUG RNA sequence within the DMPK gene. This repeat RNA is "toxic" to normal cellular function by sequestering and altering the activity of needed splicing factors for normal neuromuscular function. We are taking an approach to identify small molecules that will bind to the expanded CUG RNA repeat to prevent sequestration of splicing factors and repair the abnormal splicing phonotype in cells. To this end we have identified 2 chemical series of small molecules with clear structure activity relationships for CUG RNA binding and rescue of abnormal splicing in a DM1 cell model. In this proposal, we aim to optimize the structural features of the series to find more potent binders and splicing rescue molecules. To do this we will utilize our extensive knowledge and tools related to RNA structure and small molecule interactions and bring it to bear on targeted medicinal chemistry. DM1 represents a major unmet medical need and patients are in need of new drugs to slow or eliminate the neuromuscular deterioration
Public Health Relevance Statement: Public Health Relevance: Myotonic dystrophy 1 (DM1) is a progressive neuromuscular disease in adults with no known cure. Nymirum has identified molecules with biological activity to alleviate the disease and will be optimizing them for better activity and drg development purposes.
Project Terms: 3' Untranslated Regions; Adult; Affect; Affinity; Alternative Splicing; analog; base; Binding (Molecular Function); Biochemical; Biological; Biological Assay; Biological Availability; Cardiac; Cell model; Cell physiology; Cells; Chemicals; Chronic; Clinical; Collaborations; Custom; Data; Defect; design; Deterioration; Development; Disease; Docking; drug discovery; Exhibits; Fluorescence Polarization; Functional disorder; functional group; Genes; Health; improved; In Vitro; in vitro testing; in vivo; Individual; innovation; Insulin Receptor; interest; Knowledge; Lead; Ligand Binding; Measures; Mediating; Medical; meetings; Minor; Modeling; Modification; Monitor; mouse model; Muscle; Muscular Dystrophies; Myotonia; Myotonic Dystrophy; neuromuscular; Neuromuscular Diseases; neuromuscular function; Normal Range; novel; Nuclear; Oral; Parents; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; prevent; Process; Program Development; Property; Protein Kinase; Proteins; repaired; research study; Resolution; RNA; RNA Binding; RNA Sequences; RNA Splicing; Safety; scaffold; Scheme; Series; Site; Small Business Innovation Research Grant; small molecule; Specificity; Structure; Structure-Activity Relationship; success; Testing; tool; Toxic effect; Ursidae Family; Validation; Virtual Library; Work
