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

ChemMedChem. 2014 Nov;9(11):2455-62. doi: 10.1002/cmdc.201402095. Epub 2014 Jun 17.

Abstract

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.

Keywords: DM2 therapeutics; bisamidinium; myotonic dystrophy; triaminopyrimidine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acridines / chemistry
  • Cell Survival / drug effects
  • HeLa Cells
  • Humans
  • Imidazoles / chemistry
  • Inhibitory Concentration 50
  • Intercalating Agents / chemistry*
  • Intercalating Agents / metabolism
  • Intercalating Agents / toxicity
  • Kinetics
  • Ligands
  • Microsatellite Repeats
  • Microscopy, Confocal
  • Myotonic Dystrophy / metabolism
  • Myotonic Dystrophy / pathology
  • Pyrimidines / chemistry
  • RNA / chemistry*
  • RNA / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • Acridines
  • Imidazoles
  • Intercalating Agents
  • Ligands
  • MBNL1 protein, human
  • Pyrimidines
  • RNA-Binding Proteins
  • bisamidinium
  • RNA
  • pyrimidine