A novel CUG^exp·MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUG^exp) that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUG^exp RNA is a validated drug target for this currently untreatable disease. Herein, we develop a bioactive small molecule (1) that targets CUG^exp RNA and is able to inhibit the CUG^exp·MBNL1 interaction in cells that model DM1. The core of this small molecule is based on ligand 2, which was previously reported to be active in an in vitro assay. A polyamine-derivative side chain was conjugated to this core to make it aqueous-soluble and cell-penetrable. In a DM1 cell model this conjugate was found to disperse CUG^exp ribonuclear foci, release MBNL1, and partially reverse the mis-splicing of the insulin receptor pre-mRNA. Direct evidence for ribonuclear foci dispersion by this ligand was obtained in a live DM1 cell model using time-lapse confocal microscopy.