2. Academic Validation
  3. Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer

Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2018 Feb 25:146:354-367. doi: 10.1016/j.ejmech.2018.01.056.
Yuqi Lin 1,  Rong Liu 2,  Ping Zhao 3,  Jinxiang Ye 1,  Zheng Zheng 1,  Jingan Huang 1,  Yingying Zhang 1,  Yu Gao 1,  Haiying Chen 4,  Suling Liu 5,  Jia Zhou 6,  Ceshi Chen 7,  Haijun Chen 8
Affiliations

Affiliations

  • 1 College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. Electronic address: liurong@mail.kiz.ac.cn.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
  • 4 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
  • 5 Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 6 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
  • 7 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. Electronic address: chenc@mail.kiz.ac.cn.
  • 8 College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China. Electronic address: chenhaij@gmail.com.
PMID: 29407962 DOI: 10.1016/j.ejmech.2018.01.056
Abstract

Triple-negative breast Cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting Cancer cell Apoptosis by inhibiting KLF5 expression. Nevertheless, its Anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the Anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive Anticancer profile against TNBC via suppressing KLF5 expression.

Keywords

KLF5 expression; Mifepristone derivatives; Sensitive metabolic region; Triple-negative breast cancer.

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