| Autor: |
Klara Kohoutova, Vojtěch Dočekal, Michael J. Ausserlechner, Nora Kaiser, Andrej Tekel, Raju Mandal, Matej Horvath, Veronika Obsilova, Jan Vesely, Judith Hagenbuchner, Tomas Obsil |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
ACS Omega. 7:34632-34646 |
| ISSN: |
2470-1343 |
| Popis: |
Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accordingly, FOXO3 inhibition is a promising strategy for boosting antitumor immune responses and suppressing FOXO3-mediated therapy resistance in cancer cells. However, no FOXO3 inhibitors are currently available for clinical use. Nevertheless, we have recently identified (4-propoxy)phenylpyrimidinylguanidine as a FOXO3 inhibitor in cancer cells in the low micromolar range. Here, we report the synthesis and structure-activity relationship study of a small library of its derivatives, some of which inhibit FOXO3-induced gene transcription in cancer cells in a submicromolar range and are thus 1 order of magnitude more potent than their parent compound. By NMR and molecular docking, we showed that these compounds differ in their interactions with the DNA-binding domain of FOXO3. These results may provide a foundation for further optimizing (4-propoxy)phenylpyrimidinylguanidine and developing therapeutics for inhibiting the activity of forkhead box (FOX) transcription factors and their interactions with other binding partners. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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