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

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

  • Bioorg Med Chem. 2022 Jan 1;53:116521. doi: 10.1016/j.bmc.2021.116521.
Yuri A Piven 1,  Margarita A Yastrebova 2,  Alvina I Khamidullina 2,  Alexander M Scherbakov 3,  Victor V Tatarskiy 2,  Julia A Rusanova 4,  Alexander V Baranovsky 1,  Veronica G Zinovich 1,  Tatyana S Khlebnicova 1,  Fedor A Lakhvich 1
Affiliations

Affiliations

  • 1 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Akad. Kuprevicha st. 5/2, Minsk 220141, Belarus.
  • 2 Institute of Gene Biology, Russian Academy of Sciences, Moscow, Vavilova st. 34/5, Moscow 119334, Russian Federation.
  • 3 Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye sh. 24, Moscow 115522, Russian Federation.
  • 4 Taras Shevchenko National University of Kyiv, 64/13, Volodymyrska str., Kyiv 01601, Ukraine.
PMID: 34844036 DOI: 10.1016/j.bmc.2021.116521
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 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.

Keywords

Antiproliferative activity; Apoptosis; Benzisoxazoles; Breast cancer; Docking; HER2/neu (ERBB2); HSP90; O-acyloximes; Virtual screening.

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