Novel O-acylated (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-one oximes targeting HSP90-HER2 axis in breast cancer cells

• Published in: Bioorganic & medicinal chemistry Vol. 53; p. 116521
• Main Authors: Piven, Yuri A., Yastrebova, Margarita A., Khamidullina, Alvina I., Scherbakov, Alexander M., Tatarskiy, Victor V., Rusanova, Julia A., Baranovsky, Alexander V., Zinovich, Veronica G., Khlebnicova, Tatyana S., Lakhvich, Fedor A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2022
• Subjects: Acylation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis; Benzisoxazoles; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Docking; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; HER2/neu (ERBB2); HSP90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Models, Molecular; Molecular Structure; O-acyloximes; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Structure-Activity Relationship; Virtual screening; HSP90; Antiproliferative activity; HER2/neu (ERBB2); Benzisoxazoles; Virtual screening; Docking; Breast cancer; O-acyloximes; Apoptosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116521

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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 IC50 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.