Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance

  • Eur J Med Chem. 2020 Nov 15;206:112689. doi: 10.1016/j.ejmech.2020.112689.
Xin Lin  1 ,  Hua Xiang  2 ,  Guoshun Luo  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 3. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 32829249 DOI: 10.1016/j.ejmech.2020.112689
Abstract

Estrogen receptor alfa (ERα) is expressed in approximate 70% of breast Cancer (BC) which is the most common malignancy in women worldwide. To date, the foremost intervention in the treatment of ER positive (ER+) BC is still the endocrine therapy. However, resistance to endocrine therapies remains a major hurdle in the long-term management of ER + BC. Although the mechanisms underlying endocrine resistance are complex, cumulative evidence revealed that ERα still plays a critical role in driving BC tumor cells to grow in resistance state. Fulvestrant, a selective Estrogen receptor Degrader (SERD), has moved to first line therapy for metastatic ER + BC, suggesting that removing ERα would be a useful strategy to overcome endocrine resistance. Proteolysis-Targeting Chimera (PROTAC) technology, an emerging paradigm for protein degradation, has the potential to eliminate both wild type and mutant ERα in breast Cancer cells. Excitingly, ARV-471, an ERα-targeted PROTAC developed by Arvinas, has been in phase 1 clinical trials. In this review, we will summarize recent progress of ER-targeting PROTACs from publications and patents along with their therapeutic opportunities for the treatment of endocrine-resistant BC.

Keywords
Breast cancer (BC); Endocrine resistance; Estrogen receptor (ER); Proteolysis targeting chimeras (PROTACs).
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