Gold‐Based Pharmacophore Inhibits Intracellular MYC Protein.

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. [ABSTRACT FROM AUTHOR]