MYCMI-7: A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• MYC family oncogenes are frequently deregulated in human cancers, correlating with aggressive disease.
• MYC is a critical cancer target but has been considered
• undruggable
• due to a lack of specific inhibitors.
• MYC oncogene inhibition is a significant unmet need in cancer therapy.

Purpose of the Study:

• To evaluate MYCMI-7, a novel molecule inhibiting MYC:MAX interaction, as a potential anti-cancer therapeutic.
• To assess the efficacy and selectivity of MYCMI-7 in preclinical cancer models.
• To investigate the therapeutic potential of MYCMI-7 for MYC-driven cancers.

Main Methods:

• In vitro assays to confirm MYC:MAX interaction inhibition and MYC binding.
• Cell-based studies assessing MYC/MYCN protein degradation and transcriptional activity.
• RNA sequencing to analyze global pathway modulation.
• Ex vivo culture of patient-derived tumor cells (glioblastoma, AML).
• In vivo studies using mouse models of AML, breast cancer, and neuroblastoma.

Main Results:

• MYCMI-7 selectively inhibits MYC:MAX and MYCN:MAX interactions, binds MYC, and reduces MYC-driven transcription.
• MYCMI-7 induces MYC/MYCN protein degradation, leading to tumor cell growth arrest and apoptosis.
• High efficacy observed in patient-derived glioblastoma and AML cultures, with sensitivity correlating to MYC expression.
• Normal cells undergo G1 arrest without apoptosis, indicating a favorable safety profile.
• Significant tumor growth inhibition and prolonged survival in vivo across multiple MYC-driven cancer models with minimal side effects.

Conclusions:

• MYCMI-7 is a potent and selective inhibitor of the MYC pathway.
• MYCMI-7 demonstrates significant anti-tumor activity in preclinical models of MYC-driven cancers.
• MYCMI-7 holds promise as a clinically relevant drug candidate for treating cancers dependent on MYC/MYCN.