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MYCMI-7 :
MYCMI-7 : A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
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- Castell, Alina (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Yan, Qinzi (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Fawkner, Karin (författare)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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- Bazzar, Wesam (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Zhang, Fan (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Wickström, Malin (författare)
- Karolinska Institutet
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- Alzrigat, Mohammad (författare)
- Karolinska Institutet
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- Franco, Marcela (författare)
- Karolinska Institutet
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- Krona, Cecilia, 1976- (författare)
- Uppsala universitet,Neuroonkologi och neurodegeneration
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- Cameron, Donald P. (författare)
- Karolinska Institutet
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- Dyberg, Cecilia (författare)
- Karolinska Institutet
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- Olsen, Thale Kristin (författare)
- Karolinska Institutet
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- Verschut, Vasiliki (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Schmidt, Linnea (författare)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Lim, Sheryl Y. (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Mahmoud, Loay (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Hydbring, Per (författare)
- Karolinska Institutet
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- Lehmann, Sören (författare)
- Karolinska Institutet
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- Baranello, Laura (författare)
- Karolinska Institutet
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- Nelander, Sven (författare)
- Uppsala universitet,Neuroonkologi och neurodegeneration
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- Johnsen, John Inge (författare)
- Karolinska Institutet
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- Larsson, Lars-Gunnar (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden (creator_code:org_t)
- American Association For Cancer Research (AACR), 2022
- 2022
- Engelska.
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Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:3, s. 182-201
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- Av författaren/redakt...
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Castell, Alina
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Yan, Qinzi
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Fawkner, Karin
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Bazzar, Wesam
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Zhang, Fan
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Wickström, Malin
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Alzrigat, Mohamm ...
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Franco, Marcela
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Krona, Cecilia, ...
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Cameron, Donald ...
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Dyberg, Cecilia
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Olsen, Thale Kri ...
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Verschut, Vasili ...
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Schmidt, Linnea
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Lim, Sheryl Y.
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Mahmoud, Loay
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Hydbring, Per
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Lehmann, Sören
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Baranello, Laura
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Nelander, Sven
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Johnsen, John In ...
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Larsson, Lars-Gu ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Cancer Research ...
- Av lärosätet
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Uppsala universitet
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Karolinska Institutet