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Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches
Open accessAbstract
Myc (avian myelocytomatosis viral oncogene homolog) represents one of the most sought after drug targets in cancer. Myc transcription factor is an essential regulator of cell growth, but in most cancers it is overexpressed and associated with treatment-resistance and lethal outcomes. Over 40 years of research and drug development efforts did not yield a clinically useful Myc inhibitor. Drugging the “undruggable” is problematic, as Myc inactivation may negatively impact its physiological functions. Moreover, Myc is a disordered protein that lacks effective binding pockets on its surface. It is well established that the Myc function is dependent on dimerization with its obligate partner, Max (Myc associated factor X), which together form a functional DNA-binding domain to activate genomic targets. Herein, we provide an overview of the knowledge accumulated to date on Myc regulation and function, its critical role in cancer, and summarize various strategies that are employed to tackle Myc-driven malignant transformation. We focus on important structure-function relationships of Myc with its interactome, elaborating structural determinants of Myc-Max dimer formation and DNA recognition exploited for therapeutic inhibition. Chronological development of small-molecule Myc-Max prototype inhibitors and corresponding binding sites are comprehensively reviewed and particular emphasis is placed on modern computational drug design methods. On the outlook, technological advancements may soon provide the so long-awaited Myc-Max clinical candidate.
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“Two compounds, VPC-70067 (191) and VPC-70063 (192) (Table 3), were ultimately obtained.472”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [472]
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“because it is an intrinsically disordered protein that lacks a defined enzymatic site or binding pocket, and thus it is not amenable to small-molecule inhibition.(48) In this context, c-MYC G4 provides an attractive target for small molecules to regulate its expression.”
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“Since MYC has no inherent enzymatic activity, it is sometimes thought to be “undruggable” [18,19].”
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“Myc amplification has been reported to various cancers, and its aberrant expression has been reported in various cancers displaying the worst prognosis (6).”
BackgroundInfluentialA novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma
Cheung, B. B., Kleynhans, A., Mittra, R., Kim, P. Y., Holien, J. K., Nagy, Z. S., Ciampa, O. C., Seneviratne, J. A., Mayoh, C., Raipuria, M., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01712-w · Cited by 30
“functional MYC domains or deep protein ‘pockets’ for drug design [3].”
BackgroundSynthetic lethality: A promising therapeutic strategy for hepatocellular carcinoma
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The many lives of Myc in the pancreatic β-cell
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“At the protein level, Myc stability is controlled by multiple ubiquitin ligases, resulting in extremely short half-life of around 20–30 min (62).”
BackgroundLong, H., Hou, Y., Li, J., Song, C., & Ge, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076816 · Cited by 27
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“Agents that inhibit Myc / Max from binding DNA have also been pursued, although they lack in vivo data and specificity towards Myc / Max [117].”
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“…oncogene by epigenome modulation using dCas9 molecular tools has already been demonstrated in two works (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929158/ IGD was targeted by dCas9-DNMT3A-3L; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441141/ ( MYC promoter was targeted by dCasX - KRAB”
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“The major oncogenic mechanisms of c-MYC are related to promotion of cell cycle, drug resistance, reprogramming of cell metabolism, and rapid proliferation [23].”
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“Although we found that 10058-F4 or OSMI-4 promoted wound healing in diabetic rats, there is still a long way to go before their clinical application due to the lack of cell selectivity [37].”
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MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation
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Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer
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Self-citationTargeting MYC: Multidimensional regulation and therapeutic strategies in oncology
Duan, Y., Liu, Z., Wang, Q., Zhang, J., Liu, J., Zhang, Z., & Li, C. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101435 · Cited by 27
“13 Due to the inherent disordered structure of the MYC protein, the design of directly targeting MYC is challenging, but it is no longer deemed as an undruggable target.”
Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution
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Drug discovery of small molecules targeting the higher-order hTERT promoter G-quadruplex
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“While this has energized research targeting the promoter G4s of “undruggable” proteins [12], the issue of ligand specificity remains [10, 13, 14].”
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NCAPG2 promotes prostate cancer malignancy and stemness via STAT3/c-MYC signaling
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“Nonetheless, owing to the intrinsically unstable conformations and essential physiological function of c-MYC, direct inhibition of c-MYC with small-molecule drugs still remains challenging [51, 52].”
BackgroundTon, A.-T., Foo, J., Singh, K., Lee, J., Kalyta, A., Morin, H., Perez, C., Ban, F., Leblanc, E., Lallous, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052588 · Cited by 17
Self-citationEngineering L7Ae for RNA-Only Delivery Kill Switch Targeting CMS2 Type Colorectal Cancer Cells
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Bromodomain Inhibitor JQ1 Provides Novel Insights and Perspectives in Rhabdomyosarcoma Treatment
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“Targeting upstream regulators or downstream effectors of Myc is also a valid approach (100, 102).”
BackgroundOronsky, B. T., Cabrales, P., Caroen, S. Z., Guo, X., Scribner, C. L., Oronsky, A. L., & Reid, T. R. (2021) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1876025 · Cited by 15
“lung carcinomas, and neuroblastoma, among others, which has previously been categorized as ‘undruggable’[21].”
BackgroundThe Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions
Nirala, B. K., & Yustein, J. T. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl37304 · Cited by 19
“MYC is intrinsically disordered, lacking a well-defined hydrophobic pocket or groove suitable for high-affinity binding by low molecular weight compounds [11,43].”
Phase separation drives tumor pathogenesis and evolution: all roads lead to Rome
Gu, X., Zhuang, A., Yu, J., Chai, P., Jia, R., & Ruan, J. (2022) · Oncogene · doi:10.1038/s41388-022-02195-z · Cited by 15
Geng, X., Zhang, Y., Li, S.-H., Liu, L., Yao, R., Liu, L., & Gao, J. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.134673 · Cited by 14
Gold‐Based Pharmacophore Inhibits Intracellular MYC Protein
Ofori, S., Gukathasan, S., & Awuah, S. G. (2020) · Chemistry - A European Journal · doi:10.1002/chem.202004962 · Cited by 15
Triple-negative Breast Cancer: Identification of circRNAs With Efficacy in PreclinicalIn VivoModels
Weidle, U. H., & Birzele, F. (2023) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20368 · Cited by 14
Sriratanasak, N., Petsri, K., Laobuthee, A., Wattanathana, W., Vinayanuwattikun, C., Luanpitpong, S., & Pithi Chanvorachote, B. (2020) · Molecular Pharmacology · doi:10.1124/mol.120.119719 · Cited by 14
“, 2017) and has been linked to almost every aspect of the oncogenic process, including orchestrating uncontrolled tumor growth and proliferation, immortalization, escape from immune surveillance, and rendering treatment resistance (Carabet et al., 2018; Zahavi andWeiner, 2019).”
BackgroundSLC35B4 Stabilizes c-MYC Protein by O-GlcNAcylation in HCC
Jiang, T., Yang, J., Yang, H.-H., Chen, W., Ji, K., Xu, Y., & Yu, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.851089 · Cited by 14
Functional inhibition of c-Myc using novel inhibitors identified through “hot spot” targeting
Singh, A. K., Kumar, P., Sarvagalla, S., Bharadwaj, T., Nayak, N., Coumar, M. S., Giri, R., & Garg, N. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101898 · Cited by 14
“The c-Myc/ MAX heterodimer is considered a hot target for cancer therapeutics as it is linked to nearly 75% of human cancer showing aggressive nature and resistance toward available chemotherapy (17, 18).”
BackgroundElhasasna, H., Khan, R., Bhanumathy, K. K., Vizeacoumar, F. S., Walke, P., Bautista, M., Dahiya, D. K., Maranda, V., Patel, H. M., Amrutha, B., et al. (2022) · Cells · doi:10.3390/cells11142246 · Cited by 13
RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5
Lee, H., Jung, J. H., Ko, H. M., Park, H., Segall, A. M., Sheffmaker, R. L., Wang, J., Frey, W. D., Pham, N., Wang, Y., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308292120 · Cited by 13
“Amplification of the c - Myc - encoding gene is correlated with poor clinical outcome and tumor aggres-siveness (11–14).”
BackgroundKhalid, K. M., Ratnayake, W. S., Apostolatos, C., & Acevedo-Duncan, M. E. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2023.1213715 · Cited by 12
“…(7). c-Myc is reported to be the center of multiple pathways, and it plays a pivotal role in cell proliferation, survival, invasion, and the apoptosis in ccRCC. MYC overexpression occurs rarely due to a direct mutation, rather, it is typically the result of upstream oncogenic signaling (8, 9).”
BackgroundYuan, X., Shao, Y.-C., Guan, X.-Q., Liu, Q., Chu, M.-F., Yang, Z., Li, H., Zhao, S., Tian, Y., Zhang, J., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2024.119716 · Cited by 13
Zhao, C., Zhao, F., Yang, L., Wang, Y., Wang, H., Fang, F., Zuo, H., Li, Z., He, G., Zhan, W., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00272 · Cited by 13
Kant, R., Yang, M., Tseng, C.-H., Yen, C., Li, W.-Y., Tyan, Y., Chen, M., Tzeng, C., Chen, W.-C., You, K., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00093 · Cited by 13
Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target
Sias, F., Zoroddu, S., Migheli, R., & Bagella, L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051973 · Cited by 14
“…It has been found to in fl uence nearly all key aspects of cancer: it promotes angiogenesis, facilitates communication with the tumor microenvironment (TME), suppresses the immune system’s ability to fi ght tumors, and even contributes to resistance against many standard therapies (Figure 4) [16–18].”
Inchworm stepping of Myc-Max heterodimer protein diffusion along DNA
Dai, L., & Yu, J. H. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.08.004 · Cited by 12
Yu, Q., Wang, P., Yang, L., Wu, Z., Li, S., Xu, Y., Wu, B., Ma, A., Gan, X., & Xu, R. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109134 · Cited by 12
Yuan, D., Li, G., Yu, L., Jiang, Y., Shi, Y., Chen, Q., Ma, X., Pham, L. V., Young, K. H., Deng, M., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.618908 · Cited by 11
“To circumvent this dilemma, a series of alternative therapeutic avenues are emerging to disrupt the MYC signaling and subsequently to antagonize its oncogenic activity (24, 25).”
BackgroundPerspectives on drug discovery strategies based on IDPs
Fuertes, G., Nevola, L., & Esteban-Martín, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816348-1.00009-0 · Cited by 11
Transcriptional regulation of MYC through G-quadruplex structures
Balaratnam, S., & Schneekloth, J. S. (2020) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2020.05.002 · Cited by 12
Gonçalves, C. D. N., da Rocha, M. N., & Marinho, E. S. (2025) · In Silico Research in Biomedicine · doi:10.1016/j.insi.2025.100164 · Cited by 10
Zhang, Y., Cai, J., Hosmane, N. S., & Zhu, Y. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116841 · Cited by 10
MYC alterations in multiple myeloma: Genetic insights and prognostic impact
Cristobal‐Vargas, S., Cuadrado, M., & Gutierrez, N. C. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101177 · Cited by 12
Ma, T. P., Izrael-Tomasevic, A., Mroue, R. M., Budayeva, H. G., Malhotra, S., Raisner, R. M., Evangelista, M., Rose, C. M., Kirkpatrick, D. S., & Yu, K. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00703 · Cited by 8
The MYCN 5′ UTR as a therapeutic target in neuroblastoma
Volegova, M. P., Brown, L. E., Banerjee, U., Dries, R., Sharma, B., Kennedy, A. L., Porco, J. A. J., & George, R. E. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114134 · Cited by 10
Gu, K. J., May, H. A., & Kang, M. H. (2024) · Frontiers in Bioscience-Scholar · doi:10.31083/j.fbs1603015 · Cited by 9
“However, the results of these in vitro studies failed to be replicated in vivo because of low bioavailability and poor pharmacokinetics [17].”
BackgroundInverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers
Chareddy, Y. S., Huggins, H. P., Sahoo, S. S., Stanland, L. J., Gutierrez-Ford, C., Whately, K. M., Edatt, L., Azam, S. H., Fleming, M. C., Im, J., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci187204 · Cited by 11
Mao, S., Zhang, X., Zhao, Y., Li, X., Wang, Z., Zhou, P., Wang, Z., Zhang, X., Hu, X., Huang, G., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07333-1 · Cited by 10
“The c-MYC protein (439 amino acids) comprises an N-terminal transactivation domain (TAD), conserved MYC homology boxes (MBs) that mediate PPIs with cofactors, and a C-terminal DNA-binding domain [148, 149].”
Xie, Y., Zhang, W., Guo, L., Kril, L. M., Begley, K. L., Sviripa, V. M., Chen, X., Liu, X., Lee, E. Y., He, D., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-1017 · Cited by 10
Metadata
- Authors
- Carabet, L. A., Rennie, P. S., & Cherkasov, A.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Cherkasov, Artem
- ORCID
- Cherkasov, Artem
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2018-12-29
- Volume
- 20
- Issue
- 1
- Pages
- 120
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC6337544
- OpenAlex
- W2907541282
- Cited by
- 172
- References
- 213
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 29 · 2023: 17 · 2022: 23 · 2021: 29 · 2020: 26 · 2019: 14
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- cIRcle (University of British Columbia) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open Collections
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- c-Myc, MYC inhibitors, undruggable targets, intrinsically disordered proteins, small molecule inhibitors, structure-function relationship, protein-protein interaction, DNA-binding domain, cancer therapy resistance, computer-aided drug design
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Protein Binding, Proto-Oncogene Proteins c-myc, Quantitative Structure-Activity Relationship, Small Molecule Libraries, Drug Discovery, Molecular Docking Simulation
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