2. Academic Validation
  3. Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer

Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer

  • Eur J Med Chem. 2021 Jul 5:219:113424. doi: 10.1016/j.ejmech.2021.113424.
Tian Xu 1,  Jifa Zhang 1,  Chengcan Yang 1,  Ryszard Pluta 2,  Guan Wang 3,  Tinghong Ye 4,  Liang Ouyang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: guan8079@163.com.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yeth1309@scu.edu.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: ouyangliang@scu.edu.cn.
PMID: 33862514 DOI: 10.1016/j.ejmech.2021.113424
Abstract

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 structure-activity 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.

Keywords

Autophagy; Pharmacophore-based virtual screening; TNBC; mTOR; mTOR inhibitors.

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