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

• Published in: Cancer research communications 2022-03, Vol.2 (3), p.182-201
• Main Authors: Castell, Alina, Yan, Qinzi, Fawkner, Karin, Bazzar, Wesam, Zhang, Fan, Wickström, Malin, Alzrigat, Mohammad, Franco, Marcela, Krona, Cecilia, Cameron, Donald P, Dyberg, Cecilia, Olsen, Thale Kristin, Verschut, Vasiliki, Schmidt, Linnéa, Lim, Sheryl Y, Mahmoud, Loay, Hydbring, Per, Lehmann, Sören, Baranello, Laura, Nelander, Sven, Johnsen, John Inge, Larsson, Lars-Gunnar
• Format: Article
• Language: English
• Subjects: Drug Discovery Technologies; Drug Targets; Gene Regulation; Medicin och hälsovetenskap; Oncogenes & Tumor Suppressors; Preclinical Models; Small Molecule Agents
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-21-0019

Deregulated expression of family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) cultures. Importantly, a variety of normal cells become G arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregulates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer. Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby hampering MYC-driven tumor cell growth in culture and while sparing normal cells.