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Updated: Dec 8, 2025

Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR
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Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC

Lydia Boike1, Alexander G Cioffi1, Felix C Majewski1

  • 1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA.

Cell Chemical Biology
|September 23, 2020
PubMed

Insights

Researchers developed a new covalent ligand, EN4, to target the MYC oncoprotein. This compound disrupts MYC

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • MYC is a critical oncogenic driver in numerous human cancers.
  • Its intrinsically disordered nature makes direct targeting challenging.
  • Targeting MYC is crucial for developing new cancer therapies.

Purpose of the Study:

  • To identify novel compounds that can disrupt MYC's DNA binding and transcriptional activity.
  • To explore the potential of targeting intrinsically disordered regions of MYC.
  • To develop a new therapeutic strategy against MYC-driven cancers.

Main Methods:

  • Cysteine-reactive covalent ligand screening was employed.
  • In vitro assays assessed MYC-DNA binding disruption.
  • In situ cellular assays evaluated MYC transcriptional activity inhibition.
  • Structure-activity relationships of identified compounds were analyzed.

Main Results:

  • A covalent ligand, EN4, was identified, targeting MYC at cysteine 171.
  • EN4 demonstrated direct targeting of MYC in cells.
  • The compound reduced MYC and MAX thermal stability.
  • EN4 inhibited MYC transcriptional activity and downregulated target genes, impairing tumorigenesis.
  • Improved potency was observed with related compounds.

Conclusions:

  • A unique, ligandable site within MYC's intrinsically disordered region was identified.
  • EN4 effectively inhibits MYC transcriptional activity and tumorigenesis.
  • This approach offers a promising strategy for targeting MYC in cancer treatment.
Keywords:
MYCactivity-based protein profilingchemoproteomicscovalent ligandcysteineintrinsically disorderedtranscription factorundruggable

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