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.