Targeting of the MYCN protein with small molecule c-MYC inhibitors

Inga Muller, Karin Larsson, Anna Frenzel, Ganna Oliynyk, Hanna Zirath, Edward V. Prochownik, Nicholas J. Westwood, Marie Arsenian Henriksson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)
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Abstract

Members of the MYC family are the most frequently deregulated oncogenes in human cancer and are often correlated with aggressive disease and/or poorly differentiated tumors. Since patients with MYCN-amplified neuroblastoma have a poor prognosis, targeting MYCN using small molecule inhibitors could represent a promising therapeutic approach. We have previously demonstrated that the small molecule 10058-F4, known to bind to the c-MYC bHLHZip dimerization domain and inhibiting the c-MYC/MAX interaction, also interferes with the MYCN/MAX dimerization in vitro and imparts anti-tumorigenic effects in neuroblastoma tumor models with MYCN overexpression. Our previous work also revealed that MYCN-inhibition leads to mitochondrial dysfunction resulting in accumulation of lipid droplets in neuroblastoma cells. To expand our understanding of how small molecules interfere with MYCN, we have now analyzed the direct binding of 10058-F4, as well as three of its analogs; #474, #764 and 10058-F4(7RH), one metabolite C-m/z 232, and a structurally unrelated c-MYC inhibitor 10074-G5, to the bHLHZip domain of MYCN. We also assessed their ability to induce apoptosis, neurite outgrowth and lipid accumulation in neuroblastoma cells. Interestingly, all c-MYC binding molecules tested also bind MYCN as assayed by surface plasmon resonance. Using a proximity ligation assay, we found reduced interaction between MYCN and MAX after treatment with all molecules except for the 10058-F4 metabolite C-m/z 232 and the non-binder 10058-F4(7RH). Importantly, 10074-G5 and 10058-F4 were the most efficient in inducing neuronal differentiation and lipid accumulation in MYCN-amplified neuroblastoma cells. Together our data demonstrate MYCN-binding properties for a selection of small molecules, and provide functional information that could be of importance for future development of targeted therapies against MYCN-amplified neuroblastoma.

Original languageEnglish
Article numbere97285
Number of pages12
JournalPLoS One
Volume9
Issue number5
DOIs
Publication statusPublished - 23 May 2014

Keywords

  • Circular-dichroism spectra
  • Secondary structure analyses
  • N-MYC
  • Neuronal differentiation
  • Neoplastic phenotype
  • MYC/MAX
  • Murine development
  • Induced apoptosis
  • Tumor dormancy
  • Neural-network

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