Inhibition of Myc transcriptional activity by a mini-protein based upon Mxd1

FEBS Lett. 2020 May;594(10):1467-1476. doi: 10.1002/1873-3468.13759. Epub 2020 Mar 11.


Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini-protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10-fold more potent than Omomyc in inhibiting Myc-driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E-Box DNA in the promoters of Myc target genes and represses Myc-mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.

Keywords: Max; Myc; Myc inhibitors; Omomyc; cancer; oncogene.

MeSH terms

  • Amino Acid Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry*
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Line
  • Cell Nucleolus / metabolism
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Humans
  • Peptide Fragments / chemistry*
  • Peptide Fragments / isolation & purification
  • Peptide Fragments / pharmacology*
  • Pol1 Transcription Initiation Complex Proteins / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Repressor Proteins / chemistry*
  • Transcription, Genetic / drug effects*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • MXD1 protein, human
  • Myc associated factor X
  • Peptide Fragments
  • Pol1 Transcription Initiation Complex Proteins
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • transcription factor UBF