Nanobody-Mediated c-MYC Degradation Inhibits Tumor Cell Progression

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The c-MYC oncogene drives cancer but is difficult to target therapeutically due to its unstructured nature.
• Effective inhibition of c-MYC is crucial for improving prognosis in various malignancies.

Purpose of the Study:

• To develop and evaluate a novel therapeutic agent, CPM4, for targeting the c-MYC oncogene.
• To investigate the mechanism of action and efficacy of CPM4 in inhibiting tumor growth.

Main Methods:

• Identification of a c-MYC binding nanobody (M4) using phage display.
• Conjugation of M4 with a cell-penetrating peptide (CPP) to create CPM4.
• In vitro and in vivo studies assessing CPM4's effects on tumor cells, including apoptosis induction and tumor growth inhibition.
• Hydrogen/deuterium exchange mass spectrometry to determine the binding epitope of CPM4 on c-MYC.

Main Results:

• CPM4 demonstrated efficient nuclear localization and reduced c-MYC levels in cancer cells, inducing apoptosis.
• CPM4 binds to the PEST sequence of c-MYC, enhancing its phosphorylation and promoting degradation.
• CPM4 disrupted the c-MYC/MAX heterodimer, downregulating downstream target genes and significantly reducing tumor growth in xenograft models.

Conclusions:

• CPM4 is a promising therapeutic candidate for targeting c-MYC-driven cancers.
• The mechanism involves promoting c-MYC degradation and disrupting its oncogenic functions.
• CPM4 shows significant potential for clinical application in oncology.