Gold-Based Pharmacophore Inhibits Intracellular MYC Protein.
Samuel OforiSailajah GukathasanSamuel G AwuahPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2021)
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.
Keyphrases
- transcription factor
- small molecule
- single cell
- induced apoptosis
- cell cycle arrest
- genome wide identification
- dna binding
- stem cells
- high throughput
- cell proliferation
- silver nanoparticles
- signaling pathway
- genome wide
- mesenchymal stem cells
- protein protein
- cancer therapy
- molecular dynamics
- amino acid
- social media
- fluorescence imaging
- single molecule