Related Experiment Video
Updated: Oct 16, 2025
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in
Jesús R Medina1, Xinrong Tian1, William H Li1
1Medicinal Science and Technology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States.
Abstract:
Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.
Insights
Researchers developed new compounds that effectively reduce c-MYC oncoprotein levels, offering a promising indirect therapeutic strategy for cancers driven by MYC overexpression. This approach bypasses the challenge of directly targeting the MYC protein.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Elevated c-MYC oncoprotein is a frequent abnormality in human cancers.
- Directly inhibiting MYC is challenging due to the absence of a druggable binding pocket.
- Previous work established an indirect strategy to reduce endogenous c-MYC protein levels.
Purpose of the Study:
- To detail the medicinal chemistry efforts focused on discovering potent, orally bioavailable compounds that reduce c-MYC levels.
- To present the development of a minimum pharmacophore model derived from structure-activity relationships.
- To highlight the property-based approach used for optimizing pharmacokinetic profiles.
Main Methods:
- Screening of compounds to identify those decreasing endogenous c-MYC protein levels in a MYC-amplified cell line.
- Medicinal chemistry optimization guided by structure-activity relationships (SAR).
- Pharmacokinetic property modulation using a property-based approach.
Main Results:
- Discovery of a novel series of compounds that phenocopy c-MYC knockdown by siRNA.
- Identification of potent, orally bioavailable compounds capable of reducing c-MYC levels.
- Development of a minimum pharmacophore model for guiding further drug design.
Conclusions:
- The study successfully identified and optimized compounds for indirect MYC inhibition.
- These orally bioavailable compounds represent a promising new therapeutic avenue for MYC-driven cancers.
- The developed pharmacophore model and optimization strategies can inform future drug discovery efforts.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...