Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53

John A. Gilleran, Xin Yu, Alan J. Blayney, Anthony F. Bencivenga, Bing Na, David J. Augeri, Adam R. Blanden, S. David Kimball, Stewart N. Loh, Jacques Y. Roberge, Darren R. Carpizo

    Research output: Contribution to journalArticlepeer-review

    3 Scopus citations

    Abstract

    We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.

    Original languageEnglish (US)
    Pages (from-to)2024-2045
    Number of pages22
    JournalJournal of medicinal chemistry
    Volume64
    Issue number4
    DOIs
    StatePublished - Feb 25 2021

    All Science Journal Classification (ASJC) codes

    • Molecular Medicine
    • Drug Discovery

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