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A selective high af...
A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation
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Castell, A (författare)
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Yan, QZ (författare)
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Fawkner, K (författare)
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- Hydbring, P (författare)
- Karolinska Institutet
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- Zhang, F (författare)
- Karolinska Institutet
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Verschut, V (författare)
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- Franco, M (författare)
- Karolinska Institutet
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- Zakaria, SM (författare)
- Karolinska Institutet
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- Bazzar, W (författare)
- Karolinska Institutet
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Goodwin, J (författare)
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- Zinzalla, G (författare)
- Karolinska Institutet
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- Larsson, LG (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2018-07-03
- 2018
- Engelska.
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 10064-
- Relaterad länk:
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https://www.nature.c...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- MYC is a key player in tumor development, but unfortunately no specific MYC-targeting drugs are clinically available. MYC is strictly dependent on heterodimerization with MAX for transcription activation. Aiming at targeting this interaction, we identified MYCMI-6 in a cell-based protein interaction screen for small inhibitory molecules. MYCMI-6 exhibits strong selective inhibition of MYC:MAX interaction in cells and in vitro at single-digit micromolar concentrations, as validated by split Gaussia luciferase, in situ proximity ligation, microscale thermophoresis and surface plasmon resonance (SPR) assays. Further, MYCMI-6 blocks MYC-driven transcription and binds selectively to the MYC bHLHZip domain with a KD of 1.6 ± 0.5 μM as demonstrated by SPR. MYCMI-6 inhibits tumor cell growth in a MYC-dependent manner with IC50 concentrations as low as 0.5 μM, while sparing normal cells. The response to MYCMI-6 correlates with MYC expression based on data from 60 human tumor cell lines and is abrogated by MYC depletion. Further, it inhibits MYC:MAX interaction, reduces proliferation and induces massive apoptosis in tumor tissue from a MYC-driven xenograft tumor model without severe side effects. Since MYCMI-6 does not affect MYC expression, it is a unique molecular tool to specifically target MYC:MAX pharmacologically and it has good potential for drug development.
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- Av författaren/redakt...
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Castell, A
-
Yan, QZ
-
Fawkner, K
-
Hydbring, P
-
Zhang, F
-
Verschut, V
-
visa fler...
-
Franco, M
-
Zakaria, SM
-
Bazzar, W
-
Goodwin, J
-
Zinzalla, G
-
Larsson, LG
-
visa färre...
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Scientific repor ...
- Av lärosätet
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Karolinska Institutet