2. Academic Validation
  3. A novel selective estrogen receptor degrader induces cell cycle arrest in breast cancer via ERα degradation and the autophagy-lysosome pathway

A novel selective estrogen receptor degrader induces cell cycle arrest in breast cancer via ERα degradation and the autophagy-lysosome pathway

  • Bioorg Med Chem. 2023 Mar 7;82:117235. doi: 10.1016/j.bmc.2023.117235.
Jiawei Zhou 1,  Rong Shen 1,  Jing Liu 1,  Xiangping Deng 2,  Lilan Xin 3,  Hai-Bing Zhou 4,  Jian Huang 5
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Bayi Road, Wuhan, Hubei 430072, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Bayi Road, Wuhan, Hubei 430072, China; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Donghu Road, Wuhan 430071, China.
  • 3 State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Donghu Road, Wuhan 430071, China.
  • 4 State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Donghu Road, Wuhan 430071, China. Electronic address: zhouhb@whu.edu.cn.
  • 5 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Bayi Road, Wuhan, Hubei 430072, China. Electronic address: jianhuang@whu.edu.cn.
PMID: 36905762 DOI: 10.1016/j.bmc.2023.117235
Abstract

Breast Cancer (BC), a well-known estrogen-dependent Cancer, is the most common Cancer among women and the leading cause of Cancer deaths. One of the most important therapeutic approaches for BC is endocrine therapy targeting Estrogen Receptor alpha (ERα) and thus blocking the Estrogen Receptor signaling pathway. Drugs, such as tamoxifen or fulvestrant, are developed based on this theory and have benefited numerous patients with BC for many years. However, many patients with advanced BC, such as tamoxifen-resistant BC, cannot benefit from these developed drugs anymore. Therefore, new drugs targeting ERα are urgently needed by patients with BC. Recently, elacestrant, a novel selective Estrogen Receptor degrader (SERD), was approved by the United States Food and Drug Administration (FDA), highlighting the importance of ERα degradation in endocrine therapy. Proteolysis targeting chimera (PROTAC) has been considered a powerful technique for targeting protein degradation (TPD). In this regard, we developed and studied a novel ERα Degrader, which is a PROTAC-like SERD named 17e. We found that compound 17e can inhibit the growth of BC both in vitro and in vivo and induce the cell cycle arrest of BC. Importantly, 17e displayed no apparent toxicity toward healthy kidney and liver cells. Moreover, we observed that the presence of 17e led to a dramatic increase in the autophagy-lysosome pathway in an ERα-independent manner. Finally, we revealed that a decrease in MYC, a frequent deregulation oncogene in human cancers, was mediated by both ERα degradation and Autophagy activation in the presence of 17e. Collectively, we discovered that compound 17e induced ERα degradation and exerts significant anti-cancer effects on BC mainly through promoting the autophagy-lysosome pathway and decreasing MYC level.

Keywords

Autophagy; Breast cancer; ERα; MYC; OBHSA derivative; RNA-seq.

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