期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 219, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113424
关键词
TNBC; mTOR; Pharmacophore-based virtual screening; Autophagy; mTOR inhibitors
资金
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2018ZX09735005]
- National Natural Science Foundation of China [81922064, 81874290, 81903502]
- China Postdoctoral Science Foundation [2020M673268]
- Fundamental Research Funds for the Central Universities [2021SCU12102]
- State Key Laboratory of Esophageal Cancer Prevention and Treatment(Zhengzhou University) [K2020-001]
This study identified a potential compound for treating triple negative breast cancer by screening mTOR inhibitors and studying their related activities. The compound was found to induce apoptosis and autophagic cell death in cancer cells, providing new insights for future drug development for TNBC treatment.
Triple negative breast cancer (TNBC) has a worse prognosis than other types of breast cancer due to its special biological behavior and clinicopathological characteristics. TNBC cell proliferation and progression to metastasis can be suppressed by inducing cytostatic autophagy. mTOR is closely related to autophagy and is involved in protein synthesis, nutrient metabolism and activating mTOR promotes tumor growth and metastasis. In this paper, we adopted the strategy of structure simplification, aimed to look for novel small-molecule inhibitors of mTOR by pharmacophore-based virtual screening and biological activity determination. We found a lead compound with 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide for rational drug design and structural modification, then studied its structureactivity relationship. After that, compound 7c with the best TNBC cells inhibitory activities and superior mTOR enzyme inhibitory activity was obtained. In addition, we found that compound 7c could induce autophagic cell death and apoptosis in MDA-MB-231 and MDA-MB-468 cell lines. In conclusion, these findings provide new clues for our 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives, which are expected to become drug candidates for the treatment of TNBC in the future. (C) 2021 Elsevier Masson SAS. All rights reserved.
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