Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth

Oncogene. 2017 Dec 7;36(49):6830-6837. doi: 10.1038/onc.2017.275. Epub 2017 Aug 14.


Developing therapeutics to effectively inhibit the MYC oncoprotein would mark a key advance towards cancer patient care as MYC is deregulated in over 50% of human cancers. MYC deregulation is correlated with aggressive disease and poor patient outcome. Despite strong evidence in mouse models that inhibiting MYC would significantly impact tumour cell growth and patient survival, traditional approaches have not yet yielded the urgently needed therapeutic agents that directly target MYC. MYC functions through its interaction with MAX to regulate gene transcription by binding to E-box DNA response elements of MYC target genes. Here we used a structure-based strategy to design ME47, a small minimalist hybrid protein (MHP) able to disrupt the MAX:E-box interaction/binding and block transcriptional MYC activity. We show that inducing ME47 expression in established tumour xenografts inhibits tumour growth and decreases cellular proliferation. Mechanistically, we show by chromatin immunoprecipitation that ME47 binds to E-box binding sites of MYC target genes. Moreover, ME47 occupancy decreases MYC:DNA interaction at its cognate E-box binding sites. Taken together, ME47 is a prototypic MHP inhibitor that antagonizes tumour cell growth in vitro and in vivo and inhibits the interaction of MYC with DNA E-box elements. These results support ME47's role as a MYC inhibitor and suggest that MHPs provide an alternative therapeutic targeting system that can be used to target transcription factors important in human diseases, including cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • E-Box Elements / genetics*
  • HEK293 Cells
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Nucleotide Motifs / genetics*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays / methods*


  • Peptide Fragments
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • omomyc protein