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 language | English |
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Pages (from-to) | 4168-4175 |
Number of pages | 8 |
Journal | Chemistry - A European Journal |
Volume | 27 |
Issue number | 12 |
DOIs | |
State | Published - 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
- General Chemistry
- Catalysis
- Organic Chemistry