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  3. Design, synthesis and biological evaluation of novel dual-acting modulators targeting both estrogen receptor α (ERα) and lysine-specific demethylase 1 (LSD1) for treatment of breast cancer

Design, synthesis and biological evaluation of novel dual-acting modulators targeting both estrogen receptor α (ERα) and lysine-specific demethylase 1 (LSD1) for treatment of breast cancer

  • Eur J Med Chem. 2020 Jun 1;195:112281. doi: 10.1016/j.ejmech.2020.112281.
Ming He 1,  Wentao Ning 1,  Zhiye Hu 1,  Jian Huang 2,  Chune Dong 3,  Hai-Bing Zhou 4
Affiliations

Affiliations

  • 1 Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
  • 2 College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 3 Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: cdong@whu.edu.cn.
  • 4 Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: zhouhb@whu.edu.cn.
PMID: 32283297 DOI: 10.1016/j.ejmech.2020.112281
Abstract

Breast Cancer is a multi-factor disease, thus more and more drug combination therapies are applied in the treatment. However, there are undeniable disadvantages in drug combination therapy. Therefore, the development of new dual-targeting drugs has become a new strategy. In this study, we have developed a series of dual-acting agents targeting both Estrogen Receptor α (ERα) and Histone Demethylase based on a privileged OBHS pharmacophore scaffold developed previously by our laboratory. These novel OBHS-LSD1i conjugates showed excellent ERα binding affinity and selectivity, and exhibited potent inhibitory activity against lysine specific demethylase 1 (LSD1). Several conjugates showed higher antiproliferative efficacy in MCF-7 breast Cancer cell line compared to 4-hydroxytamoxifen in vitro. Among them, the best compound 11g displayed potent inhibitory activity against LSD1 and MCF-7 cells with IC50 values of 1.55 μM and 8.79 μM, respectively. Flow cytometry analysis of Apoptosis of 11g suggested that the effect of this type compounds on MCF-7 cells is partly caused by inducing Apoptosis. Moreover, the molecular docking of 11g with ERα and the active site of LSD1/CoREST complex provides practical way for understanding the dual mechanism actions of this kind of compounds with the targets. As such, these compounds have shown potential to become promising leads for the development of highly efficient dual-acting modulators for breast Cancer therapies.

Keywords

Breast cancer; Estrogen receptor; Lysine specific demethylase 1; OBHS-LSD1i conjugates; Selective estrogen receptor modulators.

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