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Designer Frankenproteins That Halt the Proliferation of Myc-Driven Cancer Cells

Maryam Ali1, Raneem Akel1, Francine He2

  • 1Department of Chemistry, University of Toronto, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.

Journal of Medicinal Chemistry
|September 3, 2025
PubMed

Insights

Researchers designed novel proteins to target the MYC (pronounced "my-c") proto-oncogene, crucial in many cancers. These proteins effectively reduced cancer cell viability in MYC-dependent breast cancer models, showing promise for new cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Protein Engineering

Background:

  • The proto-oncogene MYC is overexpressed in over 70% of human cancers, particularly breast cancer.
  • MYC functions by partnering with the transcription factor Max to bind DNA's E-box response element.
  • Targeting MYC is a significant goal for developing novel cancer therapies.

Purpose of the Study:

  • To design and characterize novel proteins capable of specifically binding to the E-box DNA element.
  • To evaluate the efficacy of these designed proteins in downregulating MYC target genes in breast cancer cells.
  • To assess the therapeutic potential of these proteins in inhibiting cancer cell viability.

Main Methods:

  • Designed frankenproteins (MEF and MEF/C93) based on the Max transcription factor's DNA-binding motif.
  • Utilized bacterial one-hybrid assays and quantitative electrophoretic mobility shift assays (EMSA) to assess DNA binding specificity and affinity.
  • Employed quantitative PCR to measure the downregulation of MYC target genes.
  • Performed fluorescence colocalization studies to confirm nuclear transport.
  • Assessed protein efficacy using cell viability assays (IC50 determination).

Main Results:

  • MEF and MEF/C93 proteins demonstrated specific and high-affinity binding to the E-box, comparable to native transcription factors (Kd = 8 nM).
  • These proteins selectively downregulated MYC target genes in MYC-dependent MDA-MB-231 breast cancer cells, but not in MYC-independent MCF-7 cells.
  • The designed proteins were successfully transported into the cell nuclei.
  • Significantly lower IC50 values (1-2 μM) were observed in MDA-MB-231 cells compared to MCF-7 cells (∼25 μM), indicating selective toxicity.

Conclusions:

  • The designed MEF and MEF/C93 proteins specifically target MYC-dependent cancer cells.
  • These findings represent a significant advancement in developing protein-based therapeutics for MYC-driven cancers.
  • This study validates a protein-engineering approach for targeted cancer therapy.

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