1. Novel O-acylated (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-one oximes targeting HSP90-HER2 axis in breast cancer cells.
- Author
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Piven YA, Yastrebova MA, Khamidullina AI, Scherbakov AM, Tatarskiy VV, Rusanova JA, Baranovsky AV, Zinovich VG, Khlebnicova TS, and Lakhvich FA
- Subjects
- Acylation, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, HSP90 Heat-Shock Proteins metabolism, Humans, Models, Molecular, Molecular Structure, Oxazoles chemical synthesis, Oxazoles chemistry, Oximes chemical synthesis, Oximes chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, HSP90 Heat-Shock Proteins antagonists & inhibitors, Oxazoles pharmacology, Oximes pharmacology
- Abstract
Novel O-acylated (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-one oximes were designed as potential HSP90 inhibitors. A series of the compounds was synthesized by oximation of (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-ones followed by O-acylation with acylamidobenzoic acids. The obtained compounds showed an antiproliferative effect on three breast cancer cell lines (MCF7, MDA-MB-231 and HCC1954). Compound 16s exhibited high antiproliferative potency against HCC1954 breast cancer cells with the IC
50 value of 6 µM was selected for in-depth evaluation. Compound 16s did not inhibit the growth of normal epithelial cells. We have demonstrated that the compound 16s can induce apoptosis in cancer cells via inhibition of HSP90 "client" proteins including a key oncogenic receptor, HER2/neu. Described here compounds can be considered for further basic and preclinical investigation as a part of HSP90/HER2-targeted therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2022
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