A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome

ACS Chem Biol. 2012 Oct 19;7(10):1711-8. doi: 10.1021/cb300135h. Epub 2012 Sep 4.


The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia / drug therapy*
  • Binding, Competitive / drug effects
  • COS Cells
  • Cell Nucleus / drug effects
  • Chlorocebus aethiops
  • Fragile X Syndrome / drug therapy*
  • Protein Binding
  • RNA / drug effects*
  • RNA Splicing
  • Repetitive Sequences, Nucleic Acid / drug effects*
  • Small Molecule Libraries
  • Tremor / drug therapy*


  • Small Molecule Libraries
  • RNA

Supplementary concepts

  • Fragile X Tremor Ataxia Syndrome