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MYCMI-7: A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
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2022 (English)In: Cancer Research Communications, E-ISSN 2767-9764, Vol. 2, no 3, p. 182-201Article in journal (Refereed) Published
Abstract [en]

Deregulated expression of MYC 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) ex vivo cultures. Importantly, a variety of normal cells be- come G1 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 downregu- lates 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.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2022. Vol. 2, no 3, p. 182-201
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-512478DOI: 10.1158/2767-9764.CRC-21-0019ISI: 001033814700001PubMedID: 36874405OAI: oai:DiVA.org:uu-512478DiVA, id: diva2:1801305
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2023-09-29 Created: 2023-09-29 Last updated: 2023-10-05Bibliographically approved

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Krona, CeciliaNelander, Sven

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Wickström, MalinAlzrigat, MohammadKrona, CeciliaMahmoud, LoayNelander, Sven
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Neurooncology and neurodegenerationDepartment of Immunology, Genetics and Pathology
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