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

L C Lustig1, D Dingar1, W B Tu1,2

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Oncogene
|August 15, 2017
PubMed

Insights

A novel protein, ME47, effectively inhibits the MYC oncoprotein by disrupting its DNA binding, offering a new therapeutic strategy for cancers with MYC deregulation. This approach shows promise in reducing tumor growth and cellular proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • MYC oncoprotein deregulation is prevalent in over 50% of human cancers, correlating with aggressive disease and poor outcomes.
  • Directly targeting MYC has been challenging, despite its critical role in tumor cell growth and survival.
  • MYC regulates gene transcription via interaction with MAX and binding to E-box DNA elements.

Purpose of the Study:

  • To design and evaluate a novel therapeutic agent, ME47, a minimalist hybrid protein (MHP), to inhibit MYC transcriptional activity.
  • To investigate ME47's mechanism of action in disrupting the MYC:MAX:DNA interaction.
  • To assess ME47's efficacy in inhibiting tumor growth and proliferation in preclinical models.

Main Methods:

  • Structure-based drug design was employed to create ME47, a small minimalist hybrid protein.
  • Chromatin immunoprecipitation (ChIP) was used to determine ME47's binding to MYC target gene E-box elements.
  • Tumor xenograft models were utilized to evaluate ME47's effect on tumor growth and cellular proliferation in vivo.

Main Results:

  • ME47 successfully disrupts the MAX:E-box interaction, blocking MYC transcriptional activity.
  • Induction of ME47 in established tumor xenografts significantly inhibited tumor growth and decreased cellular proliferation.
  • ChIP analysis confirmed ME47 binding to E-box sites and demonstrated reduced MYC:DNA interaction.

Conclusions:

  • ME47 is a prototypic MHP inhibitor that effectively antagonizes MYC-driven tumor cell growth both in vitro and in vivo.
  • ME47 functions by inhibiting the interaction of MYC with DNA E-box elements.
  • Minimalist hybrid proteins represent a promising alternative therapeutic strategy for targeting transcription factors, including MYC, in human diseases like cancer.

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