Small molecules that target the toxic RNA in myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is caused by an expansion of CCTG repeats in the zinc-finger protein gene (ZNF9). Transcribed CCUG repeats sequester muscleblind-like protein 1 (MBNL1), an important alternative splicing regulator, preventing its normal function, leading to the disease phenotype. We describe a series of ligands that disrupt the MBNL1-r(CCUG)n interaction as potential lead agents for developing DM2 therapeutics. A previously reported triaminopyrimidine-acridine conjugate was a moderate inhibitor in vitro, however it proved to be poorly water-soluble and not cell-permeable. To improve its therapeutic potential, the new set of ligands maintained the key triaminopyrimidine recognition unit but replaced the acridine intercalator with a bisamidinium groove binder. The optimized ligands exhibit low micromolar inhibition potency to MBNL1-r(CCUG)8. Importantly, the ligands are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cytotoxicity.