Stabilizers of the Max Homodimer Identified in Virtual Ligand Screening Inhibit Myc Function
Open accessAbstract
Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expressed constitutively and can form unstable homodimers. We have isolated stabilizers of the Max homodimer by applying virtual ligand screening (VLS) to identify specific binding pockets for small molecule interactors. Candidate compounds found by VLS were screened by fluorescence resonance energy transfer, and from these screens emerged a potent, specific stabilizer of the Max homodimer. In vitro binding assays demonstrated that the stabilizer enhances the formation of the Max-Max homodimer and interferes with the heterodimerization of Myc and Max in a dose-dependent manner. Furthermore, this compound interferes with Myc-induced oncogenic transformation, Myc-dependent cell growth, and Myc-mediated transcriptional activation. The Max-Max stabilizer can be considered a lead compound for the development of inhibitors of the Myc network.
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Analytical ultracentrifuge experiments have demonstrated that NSC13728 shifts the monomer/dimer equilibrium of Max towards the dimer and reduces the dissociation constant of Max-Max homodimers by 1000-fold.
“Analytical ultracentrifuge experiments have demonstrated that NSC13728 shifts the monomer/dimer equilibrium of Max towards the dimer and reduces the dissociation constant of Max-Max homodimers by 1000-fold.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [423]
In 2009, Jiang et al. reported the development of NSC13728, a symmetrical small molecule that stably inhibits c-Myc-regulated oncogenic transformation, cell growth, and target gene transcription through the stabilization of Max-Max homodimers.
“In 2009, Jiang et al. reported the development of NSC13728, a symmetrical small molecule that stably inhibits c-Myc-regulated oncogenic transformation, cell growth, and target gene transcription through the stabilization of Max-Max homodimers.423”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [423]
NSC13728 significantly inhibited the oncogenic transformation of Myc-dependent chick embryo fibroblasts and exhibited good selectivity for Src, Jun, and P3K induced transformation.
“NSC13728 significantly inhibited the oncogenic transformation of Myc-dependent chick embryo fibroblasts and exhibited good selectivity for Src, Jun, and P3K induced transformation.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [423]
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BackgroundInfluentialStabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription
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- Authors
- Jiang, H., Bower, K. E., Beuscher, A. E., Zhou, B., Bobkov, A. A., Olson, A. J., & Vogt, P. K.
- Affiliations
- Scripps Research Institute (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 76
- Issue
- 3
- Pages
- 491-502
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC2730382
- OpenAlex
- W2163228563
- Cited by
- 62
- References
- 40
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 7 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- National Institutes of Health
- National Cancer Institute (P01CA078045, CA078045)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- c-Myc, Max, Myc-Max heterodimer, virtual ligand screening, small molecule inhibitors, oncogenic transformation, transcriptional activation, Myc oncoprotein, cancer therapeutics
- MeSH terms
- Antineoplastic Agents, Binding Sites, DNA, Drug Screening Assays, Antitumor, Humans, Ligands, Protein Conformation, Transcriptional Activation, Proto-Oncogene Proteins c-myc, Electrophoretic Mobility Shift Assay, Cell Line, Tumor, Cell Proliferation, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Small Molecule Libraries, Protein Multimerization, Protein Stability
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