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Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F22%3A00562268" target="_blank" >RIV/67985823:_____/22:00562268 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11310/22:10450638

  • Result on the web

    <a href="https://doi.org/10.1021/acsomega.2c04613" target="_blank" >https://doi.org/10.1021/acsomega.2c04613</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acsomega.2c04613" target="_blank" >10.1021/acsomega.2c04613</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10608 - Biochemistry and molecular biology

Result continuities

  • Project

    <a href="/en/project/GA21-02080S" target="_blank" >GA21-02080S: Molecular basis of interaction between FOXO Forkhead transcription factors and tumor suppressor p53</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    ACS Omega

  • ISSN

    2470-1343

  • e-ISSN

    2470-1343

  • Volume of the periodical

    7

  • Issue of the periodical within the volume

    38

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    15

  • Pages from-to

    34632-34646

  • UT code for WoS article

    000862940400001

  • EID of the result in the Scopus database

    2-s2.0-85139331926