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. Epub 2020 Aug 2.


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).

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm / drug effects*
  • Estrogen Receptor alpha / metabolism*
  • Hormones / pharmacology*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Proteolysis / drug effects*


  • Estrogen Receptor alpha
  • Hormones