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  • Discovery of new ATP-competitive inhibitors of human DNA topoisomerase II▫$alpha$▫ through screening of bacterial topoisomerase inhibitors
    Skok, Žiga, farmacevt ...
    Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA ... topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase II[alpha] that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 [micro]M) and ATPase assay (IC50 = 0.43 [micro]M). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 [micro]M, respectively.
    Source: Bioorganic chemistry. - ISSN 0045-2068 (Vol. 102, 2020, str. 1-17)
    Type of material - article, component part ; adult, serious
    Publish date - 2020
    Language - english
    COBISS.SI-ID - 27357187

    Link(s):

    https://www.sciencedirect.com/science/article/pii/S0045206820313468
    DOI

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