Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations

Cancer Res. 2014 Jun 1;74(11):3104-13. doi: 10.1158/0008-5472.CAN-13-2235. Epub 2014 Mar 24.


Many of the gene mutations found in genetic disorders, including cancer, result in premature termination codons (PTC) and the rapid degradation of their mRNAs by nonsense-mediated RNA decay (NMD). We used virtual library screening, targeting a pocket in the SMG7 protein, a key component of the NMD mechanism, to identify compounds that disrupt the SMG7-UPF1 complex and inhibit NMD. Several of these compounds upregulated NMD-targeted mRNAs at nanomolar concentrations, with minimal toxicity in cell-based assays. As expected, pharmacologic NMD inhibition disrupted SMG7-UPF1 interactions. When used in cells with PTC-mutated p53, pharmacologic NMD inhibition combined with a PTC "read-through" drug led to restoration of full-length p53 protein, upregulation of p53 downstream transcripts, and cell death. These studies serve as proof-of-concept that pharmacologic NMD inhibitors can restore mRNA integrity in the presence of PTC and can be used as part of a strategy to restore full-length protein in a variety of genetic diseases.

Publication types

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

MeSH terms

  • Carrier Proteins / genetics
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line
  • Cell Line, Tumor
  • Codon, Nonsense*
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nonsense Mediated mRNA Decay / drug effects*
  • Nonsense Mediated mRNA Decay / genetics
  • RNA Helicases
  • RNA, Messenger / genetics
  • Small Molecule Libraries / pharmacology*
  • Trans-Activators / genetics
  • Tumor Suppressor Protein p53 / genetics*
  • Up-Regulation / drug effects


  • Carrier Proteins
  • Codon, Nonsense
  • RNA, Messenger
  • SMG7 protein, human
  • Small Molecule Libraries
  • TP53 protein, human
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • RNA Helicases
  • UPF1 protein, human