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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年7月6日

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

摘要

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.