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 |
|---|---|
| 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
Funding Information:We are thankful to all at the University of Kentucky who provided support for completion of the experiments detailed in this manuscript. The UK NMR Center supported by NSF (CHE‐997738). The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456) and UK Igniting Research Collaboration (IRC). For the flow cytometry experiments we would like to thank Greg Bauman, Ph.D. [UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558)]. Special thanks to Dr. Jong Hyun Kim for the Graphite Furnace Atomic Absorption Spectrometric measurements and analysis. Also, we are grateful for the use of Dr. Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC‐MS. Many thanks to the staff of the Mass Spectrometry facility, College of Arts and Sciences, University of Colorado Boulder for running the LC‐MS/MS of the complex with the peptide.
Funding Information:
We are thankful to all at the University of Kentucky who provided support for completion of the experiments detailed in this manuscript. The UK NMR Center supported by NSF (CHE-997738). The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456) and UK Igniting Research Collaboration (IRC). For the flow cytometry experiments we would like to thank Greg Bauman, Ph.D. [UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558)]. Special thanks to Dr. Jong Hyun Kim for the Graphite Furnace Atomic Absorption Spectrometric measurements and analysis. Also, we are grateful for the use of Dr. Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS. Many thanks to the staff of the Mass Spectrometry facility, College of Arts and Sciences, University of Colorado Boulder for running the LC-MS/MS of the complex with the peptide.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
Keywords
- MYC
- gold complexes
- ligand design
- lysine modification
- protein–protein interactions
ASJC Scopus subject areas
- Catalysis
- Organic Chemistry