Gold-Based Pharmacophore Inhibits Intracellular MYC Protein

Samuel Ofori, Sailajah Gukathasan, Samuel G. Awuah

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Direct targeting of intrinsically disordered proteins, including MYC, by small molecules for biomedical applications would resolve a longstanding issue in chemical biology and medicine. Thus, we developed gold-based small-molecule MYC reagents that engage MYC inside cells and modulate MYC transcriptional activity. Lead compounds comprise an affinity ligand and a gold(I) or gold(III) warhead capable of protein chemical modification. Cell-based MYC target engagement studies via CETSA and co-immunoprecipitation reveal specific interaction of compounds with MYC in cells. The lead gold(I) reagent, 1, demonstrates superior cell-killing potential (up to 35-fold) in a MYC-dependent manner when compared to 10058-F4 in cells including the TNBC, MDA-MB-231. Subsequently, 1 suppresses MYC transcription factor activity via functional colorimetric assays, and gene-profiling using whole-cell transcriptomics reveals significant modulation of MYC target genes by 1. These findings point to metal-mediated ligand affinity chemistry (MLAC) based on gold as a promising strategy to develop chemical probes and anticancer therapeutics targeting MYC.

Original languageEnglish
Pages (from-to)4168-4175
Number of pages8
JournalChemistry - A European Journal
Volume27
Issue number12
DOIs
StatePublished - Feb 24 2021

Bibliographical note

Publisher Copyright:
© 2020 Wiley-VCH GmbH

Keywords

  • MYC
  • gold complexes
  • ligand design
  • lysine modification
  • protein–protein interactions

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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