Myotonic dystrophy: candidate small molecule therapeutics

Drug Discov Today. 2017 Nov;22(11):1740-1748. doi: 10.1016/j.drudis.2017.07.011. Epub 2017 Aug 2.

Abstract

Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing, and therapeutic gene modulation.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Design*
  • Drug Repositioning
  • Gene Expression Regulation
  • High-Throughput Screening Assays / methods
  • Humans
  • Myotonic Dystrophy / drug therapy*
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / physiopathology
  • Myotonin-Protein Kinase / genetics*
  • Trinucleotide Repeats

Substances

  • DMPK protein, human
  • Myotonin-Protein Kinase