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.
Leenus Martin  1 ,  Arsen Grigoryan  1 ,  Ding Wang  1 ,  Jinhua Wang  1 ,  Laura Breda  1 ,  Stefano Rivella  1 ,  Timothy Cardozo  1 ,  Lawrence B Gardner  2
Affiliations
  • 1. Authors' Affiliations: Departments of Medicine, Biochemistry and Molecular Pharmacology; The NYU Cancer Institute, New York University School of Medicine; and Departments of Pediatrics and Cell and Biology Development, Weill Cornell School of Medicine, New York, New York.
  • 2. Authors' Affiliations: Departments of Medicine, Biochemistry and Molecular Pharmacology; The NYU Cancer Institute, New York University School of Medicine; and Departments of Pediatrics and Cell and Biology Development, Weill Cornell School of Medicine, New York, New YorkAuthors' Affiliations: Departments of Medicine, Biochemistry and Molecular Pharmacology; The NYU Cancer Institute, New York University School of Medicine; and Departments of Pediatrics and Cell and Biology Development, Weill Cornell School of Medicine, New York, New YorkAuthors' Affiliations: Departments of Medicine, Biochemistry and Molecular Pharmacology; The NYU Cancer Institute, New York University School of Medicine; and Departments of Pediatrics and Cell and Biology Development, Weill Cornell School of Medicine, New York, New York [email protected].
PMID: 24662918 DOI: 10.1158/0008-5472.CAN-13-2235
Abstract

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.

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