2. Academic Validation
  3. Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53

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

  • J Med Chem. 2021 Feb 25;64(4):2024-2045. doi: 10.1021/acs.jmedchem.0c01360.
John A Gilleran 1,  Xin Yu 2 3,  Alan J Blayney 4,  Anthony F Bencivenga 1,  Bing Na 2 3,  David J Augeri 1,  Adam R Blanden 4,  S David Kimball 1,  Stewart N Loh 4,  Jacques Y Roberge 1,  Darren R Carpizo 5 6
Affiliations

Affiliations

  • 1 Rutgers Molecular Design and Synthesis, Office of Research and Economic Development, Piscataway, New Jersey 08854, United States.
  • 2 Program of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08901, United States.
  • 3 Department of Surgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901, United States.
  • 4 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, United States.
  • 5 Division of Surgical Oncology, Department of Surgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, United States.
  • 6 Wilmot Cancer Center, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, United States.
PMID: 33538587 DOI: 10.1021/acs.jmedchem.0c01360
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.

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