Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Inhibition of tumor growth using A conjugated nanobody that specifically targets c-MYC

Oncogene volume 44, pages 3213–3224 (2025)Cite this article

Subjects

Abstract

The MYC oncogene is a frequently activated oncogene in human cancers, and its high expression is strongly correlated with a poor prognosis. The lack of conventional enzyme-binding sites in MYC poses significant challenges for the development of small-molecule-based therapies to treat MYC-deregulated cancer. In particular, only one transmembrane peptide that targets c-MYC has advanced to early clinical trials, thus highlighting the need of effective and direct approaches for targeting c-MYC in cancer treatment. In this study, we developed a conjugated nanobody (NB) that specifically targets MYC, termed a cell-permeable MYC-targeting nanobody (CPMycNB), via sortase-mediated protein ligation. CPMycNB effectively entered the nucleus and bound to c-MYC, thereby disrupting the c-MYC-MAX interaction. This disruption resulted in the downregulation of c-MYC-targeted genes, activation of apoptotic pathways, and inhibition of cell growth and proliferation in c-MYC-driven tumor cells. Using hydrogen-deuterium exchange mass spectrometry, we found that CPMycNB interacted with the leucine zipper domain of c-MYC. Furthermore, xenograft studies confirmed the therapeutic efficacy of CPMycNB, which significantly reduced tumor size and weight. Our findings highlight the potential of CPMycNB for the treatment of c-MYC-associated malignancies.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Characterization of MycNB and CPMycNB conjugates.
Fig. 2: Hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis.
Fig. 3: Effects of MycNB and CPMycNB on cancer cells.
Fig. 4: Effects of CPMycNB on c-MYC and MAX Interaction.
Fig. 5: Proteomic analysis of CPMycNB treated HCT116 cells.
Fig. 6: In vivo therapeutic efficacy of CPMycNB.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Dang CV. Myc on the path to cancer. Cell. 2012;149:22–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, et al. Pan-cancer alterations of the myc oncogene and its proximal network across the cancer genome atlas. Cell Syst. 2018;6:282–300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Wasylishen AR, Penn LZ. Myc: the beauty and the beast. Genes cancer. 2010;1:532–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Lin CY, Lovn J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-myc. Cell. 2012;151:56–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Di Giacomo S, Sollazzo M, Paglia S, Grifoni D. Myc, cell competition, and cell death in cancer: the inseparable triad. Genes. 2017;8:120.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF, Kirsch IR, et al. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature. 1985;318:69–73.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou ZQ, Hurlin PJ. The interplay between mad and myc in proliferation and differentiation. Trends cell Biol. 2001;11:S10–S14.

    Article  PubMed  CAS  Google Scholar 

  8. Bretones G, Delgado MD, Len J. Myc and cell cycle control. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2015;1849:506–16.

    Article  PubMed  CAS  Google Scholar 

  9. Llombart V, Mansour MR. Therapeutic targeting of undruggable MYC. EBioMedicine. 2022;75:103756.

    Article  PubMed  Google Scholar 

  10. Gustafson W, Weiss W. Myc proteins as therapeutic targets. Oncogene. 2010;29:1249–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Mo H, Henriksson M. Identification of small molecules that induce apoptosis in a myc-dependent manner and inhibit myc-driven transformation. Proc Natl Acad Sci. 2006;103:6344–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Duffy MJ, O’Grady S, Tang M, Crown J. Myc as a target for cancer treatment. Cancer Treat Rev. 2021;94:102154.

    Article  PubMed  CAS  Google Scholar 

  13. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. Bet bromodomain inhibition as a therapeutic strategy to target c-myc. Cell. 2011;146:904–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AMK, et al. Protac-induced bet protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci. 2016;113:7124–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Crump NT, Ballabio E, Godfrey L, Thorne R, Repapi E, Kerry J, et al. Bet inhibition disrupts transcription but retains enhancer-promoter contact. Nat Commun. 2021;12:223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, et al. Small-molecule myc inhibitors suppress tumor growth and enhance immunotherapy. Cancer cell. 2019;36:483–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, et al. Small-molecule antagonists of myc/max dimerization inhibit myc-induced transformation of chicken embryo fibroblasts. Proc Natl Acad Sci. 2002;99:3830–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Amati B. Myc degradation: dancing with ubiquitin ligases. Proc Natl Acad Sci. 2004;101:8843–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Crawford LJ, Campbell DC, Morgan JJ, Lawson MA, Down JM, Chauhan D, et al. The e3 ligase huwe1 inhibition as a therapeutic strategy to target myc in multiple myeloma. Oncogene. 2020;39:5001–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ross J, Miron CE, Plescia J, Laplante P, McBride K, Moitessier N, et al. Targeting myc: from understanding its biology to drug discovery. Eur J Med Chem. 2021;213:113137.

    Article  PubMed  CAS  Google Scholar 

  21. Donati G, Amati B. Myc and therapy resistance in cancer: risks and opportunities. Mol Oncol. 2022;16:3828–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Wang E, Sorolla A, Cunningham PT, Bogdawa HM, Beck S, Golden E, et al. Tumor penetrating peptides inhibiting myc as a potent targeted therapeutic strategy for triple-negative breast cancers. Oncogene. 2019;38:140–50.

    Article  PubMed  CAS  Google Scholar 

  23. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, et al. Modelling myc inhibition as a cancer therapy. Nature. 2008;455:679–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Demma MJ, Mapelli C, Sun A, Bodea S, Ruprecht B, Javaid S. et al. Omomyc reveals new mechanisms to inhibit the myc oncogene. Mol Cellular Biol. 2019;39:00248–19.

    Article  Google Scholar 

  25. Beaulieu ME, Jauset T, Mass-Valls D, Martnez-Martn S, Rahl P, Maltais L, et al. Intrinsic cell-penetrating activity propels omomyc from proof of concept to viable anti-myc therapy. Sci Transl Med. 2019;11:eaar5012.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Garralda E, Beaulieu ME, Moreno V, Casacuberta-Serra S, Martnez-Martn S, Foradada L, et al. Myc targeting by omo-103 in solid tumors: a phase 1 trial. Nat Med. 2024;30:762–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Muyldermans S. Nanobodies: natural single-domain antibodies. Annu Rev Biochem. 2013;82:775–97.

    Article  PubMed  CAS  Google Scholar 

  28. Muyldermans S, Atarhouch T, Saldanha J, Barbosa J, Hamers R. Sequence and structure of vh domain from naturally occurring camel heavy chain immunoglobulins lacking light chains. Protein Eng Des Selection. 1994;7:1129–35.

    Article  CAS  Google Scholar 

  29. Ji, F, Ren, J, Vincke, C, Jia, L, Muyldermans, S Nanobodies: From serendipitous discovery of heavy chain-only antibodies in camelids to a wide range of useful applications. In: Single-Domain Antibodies: Methods and Protocols. Springer. 2022:3-17.

  30. Daley-Bauer L, Purdy S, Smith M, Gagliardo L, Davis W, Appleton J. Contributions of conventional and heavy-chain igg to immunity in fetal, neonatal, and adult alpacas. Clin Vaccin Immunol. 2010;17:2007–15.

    Article  CAS  Google Scholar 

  31. Conrath K, Wernery U, Muyldermans S, Nguyen VK. Emergence and evolution of functional heavy-chain antibodies in camelidae. Dev Comp Immunol. 2003;27:87–103.

    Article  PubMed  CAS  Google Scholar 

  32. Atibalentja DF, Deutzmann A, Felsher DW. A big step for myc-targeted therapies. Trends Cancer. 2024;10:383–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Pooga M, Langel Ü. Classes of Cell-Penetrating Peptides. Methods Mol Biol. 2015;1324:3–28.

    Article  PubMed  Google Scholar 

  34. Raucher D, Ryu JS. Cell-penetrating peptides: strategies for anticancer treatment. Trends Mol Med. 2015;21:560–70.

    Article  PubMed  CAS  Google Scholar 

  35. Wolfe JM, Fadzen CM, Choo ZN, Holden RL, Yao M, Hanson GJ, et al. Machine learning to predict cell-penetrating peptides for antisense delivery. ACS Cent Sci. 2018;4:512–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kadonosono T, Yamano A, Goto T. et al. Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation. J Control Release. 2015;201:14–21.

    Article  PubMed  CAS  Google Scholar 

  37. Yu S, Yang H, Li T, Pan H, Ren S, Luo G, et al. Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo. Nat Commun. 2021;12:5131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Teo SL, Rennick JJ, Yuen D, Al-Wassiti H, Johnston AP, Pouton CW. Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay. Nat Commun. 2021;12:3721.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kent, L Targeting then-myc oncoprotein using nanobody technology. Ph.D. thesis; University of Cambridge. 2018.

  40. Mundo L, Ambrosio MR, Raimondi F, Del Porro L, Guazzo R, Mancini V, et al. Molecular switch from myc to mycn expression in myc protein negative burkitt lymphoma cases. Blood Cancer J. 2019;9:91.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang C, Zhang J, Yin J, Gan Y, Xu S, Gu Y, et al. Alternative approaches to target myc for cancer treatment. Signal Transduct Target Ther. 2021;6:117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ingvarsson S. The myc gene family proteins and their role in transformation and differentiation. Semin Cancer Biol. 1990;1:359–69.

    PubMed  CAS  Google Scholar 

  43. Theile CS, Witte MD, Blom AE, Kundrat L, Ploegh HL, Guimaraes CP. Site-specific n-terminal labeling of proteins using sortase-mediated reactions. Nat Protoc. 2013;8:1800–7.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Massa S, Vikani N, Betti C, Ballet S, Vanderhaegen S, Steyaert J, et al. Sortase a-mediated site-specific labeling of camelid single-domain antibody-fragments: a versatile strategy for multiple molecular imaging modalities. Contrast media Mol imaging. 2016;11:328–39.

    Article  PubMed  CAS  Google Scholar 

  45. Zhu WL, Shin SY. Effects of dimerization of the cell-penetrating peptide tat analog on antimicrobial activity and mechanism of bactericidal action. J Pept Sci: Publ Eur Pept Soc. 2009;15:345–52.

    Article  CAS  Google Scholar 

  46. Brooks H, Lebleu B, Vivs E. Tat peptide-mediated cellular delivery: back to basics. Adv drug Deliv Rev. 2005;57:559–77.

    Article  PubMed  CAS  Google Scholar 

  47. Zhang H, Zhang Y, Zhang C, Yu H, Ma Y, Li Z, et al. Recent advances of cell-penetrating peptides and their application as vectors for delivery of peptide and protein-based cargo molecules. Pharmaceutics. 2023;15:2093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun. 2018;9:1410.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Hsiue EHC, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, et al. Targeting a neoantigen derived from a common tp53 mutation. Science. 2021;371:eabc8697.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.

    Article  PubMed  CAS  Google Scholar 

  51. Pearlman AH, Hwang MS, Konig MF, Hsiue EHC, Douglass J, DiNapoli SR, et al. Targeting public neoantigens for cancer immunotherapy. Nat cancer. 2021;2:487–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Key Research and Development Program of China (Grant No. 2021YFA1302601), the National Natural Science Foundation of China (Grant No. 82172556), the Beijing Natural Science Foundation (IS24040), and the National Natural Science Foundation of China (Grant No. T2293763). We greatly appreciate the Facility for Protein Chemistry and Proteomics at Tsinghua University for sample analysis.

Author information

Author notes

  1. These authors contributed equally: Yuanyuan Xue, Hao Jiang.

Authors and Affiliations

  1. MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China

    Yuanyuan Xue, Hao Jiang, Ting Li, Xiaolin Tian, Zelong Miao, Zhaoyun Zong, Wenxi Ding & Haiteng Deng

  2. Department of Clinical Laboratory, Shandong Provincial Hospital, Jinan, China

    Yali Wei

  3. Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China

    Haiteng Deng

Authors
  1. Yuanyuan Xue
    View author publications

    Search author on:PubMed Google Scholar

  2. Hao Jiang
    View author publications

    Search author on:PubMed Google Scholar

  3. Ting Li
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiaolin Tian
    View author publications

    Search author on:PubMed Google Scholar

  5. Zelong Miao
    View author publications

    Search author on:PubMed Google Scholar

  6. Zhaoyun Zong
    View author publications

    Search author on:PubMed Google Scholar

  7. Wenxi Ding
    View author publications

    Search author on:PubMed Google Scholar

  8. Yali Wei
    View author publications

    Search author on:PubMed Google Scholar

  9. Haiteng Deng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

YX conceived and coordinated the entire project, designed the experiments, conducted data analysis, and authored the manuscript. HJ, TL, XT, and ZZ performed the experiments and analyzed the data. WD and YW contributed to data analysis and the interpretation of results. ZM and HD were responsible for additional data analysis and critically reviewed the manuscript.

Corresponding author

Correspondence to Haiteng Deng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xue, Y., Jiang, H., Li, T. et al. Inhibition of tumor growth using A conjugated nanobody that specifically targets c-MYC. Oncogene 44, 3213–3224 (2025). https://doi.org/10.1038/s41388-025-03486-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03486-x

This article is cited by

Search

Advanced search

Quick links