Related Experiment Video
Updated: Jan 3, 2026
A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC
Jonathan D Macdonald, Selena Chacón Simon, Changho Han
1Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37232 , United States.
Abstract:
The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.
Insights
Researchers developed a novel strategy to inhibit MYC oncogenes by blocking interactions with WD Repeat-Containing Protein 5. This approach aims to disrupt MYC
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- MYC oncogenes drive tumor growth but are challenging to target directly.
- Overexpression or amplification of MYC is common in various cancers.
- Targeting MYC's interactions with cofactors is a promising therapeutic strategy.
Purpose of the Study:
- To develop novel inhibitors targeting the MYC-WD Repeat-Containing Protein 5 (WPC5) interaction.
- To disrupt MYC's chromatin localization and oncogenic functions.
- To identify small molecules for potential cancer therapy.
Main Methods:
- High-throughput screening to identify interaction inhibitors.
- Structure-guided drug design for optimizing small molecules.
- In vitro assays to assess binding affinity and inhibitory potential.
Main Results:
- Identified potent small-molecule inhibitors of the MYC-WPC5 interaction.
- Demonstrated significant in vitro binding affinity for the identified compounds.
- Developed structurally related negative controls for further study.
Conclusions:
- Disrupting the MYC-WPC5 protein-protein interaction is a viable therapeutic strategy.
- The identified small molecules serve as starting points for developing new cancer drugs.
- This approach holds potential for treating multiple MYC-driven tumors.
Related Concept Videos
02:23Abnormal Proliferation
02:04Protein-protein Interfaces