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

被引：4
作者：
Piven, Yuri A. [1 ]
Yastrebova, Margarita A. [2 ]
Khamidullina, Alvina, I [2 ]
Scherbakov, Alexander M. [3 ]
Tatarskiy, Victor V. [2 ]
Rusanova, Julia A. [4 ]
Baranovsky, Alexander, V [1 ]
Zinovich, Veronica G. [1 ]
Khlebnicova, Tatyana S. [1 ]
Lakhvich, Fedor A. [1 ]
机构：
[1] Natl Acad Sci Belarus, Inst Bioorgan Chem, Akad Kuprevicha St 5-2, Minsk 220141, BELARUS
[2] Russian Acad Sci, Inst Gene Biol, Vavilova St 34, Moscow 119334, Russia
[3] Blokhin NN Natl Med Res Ctr Oncol, Dept Expt Tumor Biol, Kashirskoye Sh 24, Moscow 115522, Russia
[4] Taras Shevchenko Natl Univ Kyiv, 64-13 Volodymyrska Str, UA-01601 Kiev, Ukraine
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2022年 / 53卷
基金：
俄罗斯基础研究基金会;
关键词：
Benzisoxazoles; O-acyloximes; Virtual screening; Docking; HSP90; Antiproliferative activity; Breast cancer; HER2/neu (ERBB2); Apoptosis; SHOCK-PROTEIN; 90; EPIDERMAL-GROWTH-FACTOR; PHARMACOLOGICAL EVALUATION; BIOLOGICAL EVALUATION; ANTICANCER AGENTS; INHIBITOR; DESIGN; DERIVATIVES; GELDANAMYCIN; DISCOVERY;
D O I：
10.1016/j.bmc.2021.116521
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 mu M was selected for indepth 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 pre clinical investigation as a part of HSP90/HER2-targeted therapies.
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页数：15
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