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

• Published in: Journal of medicinal chemistry Vol. 64; no. 4; pp. 2024 - 2045
• Main Authors: Gilleran, John A, Yu, Xin, Blayney, Alan J, Bencivenga, Anthony F, Na, Bing, Augeri, David J, Blanden, Adam R, Kimball, S. David, Loh, Stewart N, Roberge, Jacques Y, Carpizo, Darren R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.02.2021; Amer Chemical Soc
• Subjects: 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; Chemistry, Medicinal; Humans; Hydrazones - chemical synthesis; Hydrazones - pharmacology; Hydrazones - therapeutic use; Life Sciences & Biomedicine; Mice; Mice, Nude; Molecular Structure; Neoplasms - drug therapy; Pharmacology & Pharmacy; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Science & Technology; Structure-Activity Relationship; Tumor Suppressor Protein p53 - drug effects; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; Zinc - metabolism; 2-ACETYLPYRIDINE; SITE; 2-BENZOXAZOLYL; THIOSEMICARBAZONES; CHELATORS; COPPER; CONFORMATION; BINDING; ANTITUMOR; MOLECULES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01360

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.