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

doi:10.1021/acs.jmedchem.0c01360

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. Epub 2021 Feb 4.

Authors

John A Gilleran¹, Xin Yu^{2

3}, Alan J Blayney⁴, Anthony F Bencivenga¹, Bing Na^{2

3}, David J Augeri¹, Adam R Blanden⁴, S David Kimball¹, Stewart N Loh⁴, Jacques Y Roberge¹, Darren R Carpizo^{5

6}

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Benzothiazoles / chemical synthesis
Benzothiazoles / pharmacology
Benzothiazoles / therapeutic use*
Benzoxazoles / chemical synthesis
Benzoxazoles / pharmacology
Benzoxazoles / therapeutic use*
Cell Line, Tumor
Chelating Agents / chemical synthesis
Chelating Agents / pharmacology
Chelating Agents / therapeutic use*
Humans
Hydrazones / chemical synthesis
Hydrazones / pharmacology
Hydrazones / therapeutic use*
Mice
Mice, Nude
Molecular Structure
Neoplasms / drug therapy
Photosensitizing Agents / chemical synthesis
Photosensitizing Agents / pharmacology
Photosensitizing Agents / therapeutic use
Structure-Activity Relationship
Tumor Suppressor Protein p53 / drug effects
Tumor Suppressor Protein p53 / metabolism*
Xenograft Model Antitumor Assays
Zinc / metabolism*

Substances

Antineoplastic Agents
Benzothiazoles
Benzoxazoles
Chelating Agents
Hydrazones
Photosensitizing Agents
Tumor Suppressor Protein p53
Zinc

Abstract

Publication types

MeSH terms

Substances

Grants and funding