Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids
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// Huabo Wang 1 , Peter Teriete 2 , Angela Hu 1 , Dhanya Raveendra-Panickar 2 , Kelsey Pendelton 1 , John S. Lazo 3 , Julie Eiseman 4,5 , Toril Holien 6 , Kristine Misund 6 , Ganna Oliynyk 7 , Marie Arsenian-Henriksson 7 , Nicholas D. P. Cosford 2 , Anders Sundan 6 and Edward V. Prochownik 1,5,8 1 Section of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA 2 Cell Death and Survival Networks Research Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 3 The Department of Pharmacology, The University of Virginia School of Medicine, Charlottesville, Virginia, USA 4 The Department of Chemical Biology and Pharmacology, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA 5 The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 6 Department of Cancer Research and Molecular Medicine and The K. G. Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway 7 Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden 8 The Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA Correspondence to: Edward V. Prochownik, email: // Keywords : 10058-F4, 10074-G5, BET inhibitors, myeloma, neuroblastoma, quinone methide Received : September 24, 2015 Accepted : September 26, 2015 Published : October 14, 2015 Abstract Many oncogenic signals originate from abnormal protein-protein interactions that are potential targets for small molecule inhibitors. However, the therapeutic disruption of these interactions has proved elusive. We report here that the naturally-occurring triterpenoid celastrol is an inhibitor of the c-Myc (Myc) oncoprotein, which is over-expressed in many human cancers. Most Myc inhibitors prevent the association between Myc and its obligate heterodimerization partner Max via their respective bHLH-ZIP domains. In contrast, we show that celastrol binds to and alters the quaternary structure of the pre-formed dimer and abrogates its DNA binding. Celastrol contains a reactive quinone methide group that promiscuously forms Michael adducts with numerous target proteins and other free sulfhydryl-containing molecules. Interestingly, triterpenoid derivatives lacking the quinone methide showed enhanced specificity and potency against Myc. As with other Myc inhibitors, these analogs rapidly reduced the abundance of Myc protein and provoked a global energy crisis marked by ATP depletion, neutral lipid accumulation, AMP-activated protein kinase activation, cell cycle arrest and apoptosis. They also inhibited the proliferation of numerous established human cancer cell lines as well as primary myeloma explants that were otherwise resistant to JQ1, a potent indirect Myc inhibitor. N-Myc amplified neuroblastoma cells showed similar responses and, in additional, underwent neuronal differentiation. These studies indicate that certain pharmacologically undesirable properties of celastrol such as Michael adduct formation can be eliminated while increasing selectivity and potency toward Myc and N-Myc. This, together with their low in vivo toxicity, provides a strong rationale for pursuing the development of additional Myc-specific triterpenoid derivatives.
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Edward et al. reported that celastrol, a naturally occurring triterpenoid compound, is an inhibitor of the c-Myc oncoprotein that is overexpressed in many human cancers.
“Edward et al. reported that celastrol (190) (Table 3), a naturally occurring triterpenoid compound, is an inhibitor of the c-Myc oncoprotein that is overexpressed in many human cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [471]
Celastrol binds to and alters the quaternary structure of the preformed dimer, thereby eliminating its DNA binding ability.
“They demonstrated that celastrol binds to and alters the quaternary structure of the preformed dimer, thereby eliminating its DNA binding ability.471”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [471]
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“The developed Myc-Max/DNA disruptors include: natural-occurring compounds, such as celastrol and celastrol-inspired triterpenoids [119]; synthetic α-mimetics, such as JKY-2-169 intentionally engineered to recognize the structurally ordered Myc and hence to disrupt Myc-Max/DNA binding [120]; small molecule inhibitors (…”
BackgroundSalvador, J. A. R., Leal, A. S., Valdeira, A. S. C., Gonçalves, B. M. F., Alho, D. P. S., Figueiredo, S. A. C., Silvestre, S., & Mendes, V. I. S. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.07.013 · Cited by 160 · see citing works
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RetractedDerivation of Genetically Defined Murine Hepatoblastoma Cell Lines with Angiogenic Potential
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BindingDB Entry 50021153: MYC the oncogene from hell: Novel opportunities for cancer therapy.
BindingDB (2025) · UC San Diego · doi:10.7270/q2qz2gkz
- Authors
- Wang, H., Teriete, P., Hu, A., Raveendra-Panickar, D., Pendelton, K., Lazo, J. S., Eiseman, J., Holien, T., Misund, K., Oliynyk, G., Arsenian-Henriksson, M., Cosford, N. D. P., Sundan, A., & Prochownik, E. V.
- Affiliations
- Children's Hospital of Pittsburgh (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Cell Death and Survival Networks Research Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- University of Virginia (US)
- UPMC Hillman Cancer Center (US)
- Norwegian University of Science and Technology (NO)
- Karolinska Institutet (SE)
- Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-10-14
- Volume
- 6
- Issue
- 32
- Pages
- 32380-32395
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4741700
- OpenAlex
- W1813072770
- Cited by
- 53
- References
- 85
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 3
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BIBSYS Brage (BIBSYS (Norway)) (acceptedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Funders
- University of Pittsburgh (P30 CA047904)
- Kreftforeningen
- National Institutes of Health
- Cancer Institute, University of Pittsburgh (P30CA047904)
- National Cancer Institute (R01CA140624, R01CA174713, P30CA047904)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- celastrol, c-Myc, Max, triterpenoids, quinone methides, protein-protein interaction inhibition, BET inhibitors, multiple myeloma, neuroblastoma, quaternary structure, small molecule inhibitors, 10058-F4
- MeSH terms
- Antineoplastic Agents, Phytogenic, Dose-Response Relationship, Drug, Humans, Neoplasms, Protein Binding, Structure-Activity Relationship, Time Factors, Transfection, Triterpenes, Tumor Cells, Cultured, Drug Design, Signal Transduction, Proto-Oncogene Proteins c-myc, Apoptosis, Protein Structure, Quaternary, Cell Line, Tumor, Cell Proliferation, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Pentacyclic Triterpenes, Protein Multimerization, Molecular Targeted Therapy, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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