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A Novel Dual-Targeting PROTAC Overcomes Endocrine Resistance by Engaging Orthosteric and Allosteric Sites of Estrogen

Chao Wang1, Bin Xu1, Lilan Xin1

  • 1Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan430071, China.

Journal of Medicinal Chemistry
|August 13, 2026
PubMed

Insights

New PROTACs targeting both ERα binding sites overcome endocrine resistance in breast cancer. This dual-targeting strategy effectively degrades ERα, inhibiting tumor growth and offering a promising approach for resistant ER+ breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Estrogen receptor alpha (ERα) is a key target for ER-positive breast cancer.
  • Resistance to endocrine therapies, often due to ERα mutations, necessitates new treatment strategies.
  • Targeting both the ligand-binding pocket (LBP) and coactivator binding site (CBS) offers a novel approach.

Purpose of the Study:

  • To design and evaluate ERα LBP/CBS dual-targeting proteolysis-targeting chimeras (PROTACs) to overcome endocrine resistance.
  • To assess the efficacy of lead compound P5 in preclinical models of ER-positive breast cancer.

Main Methods:

  • Design and synthesis of ERα LBP/CBS dual-targeting PROTACs.
  • In vitro assessment of binding affinities, antiproliferative activity, and ERα degradation.
  • Mechanistic studies including cell cycle analysis and apoptosis assays.
  • In vivo evaluation of tumor growth inhibition in a xenograft model.

Main Results:

  • Lead compound P5 showed high binding affinities for both ERα LBP and CBS.
  • P5 demonstrated potent antiproliferative effects and efficient ERα degradation via the ubiquitin-proteasome system.
  • P5 induced S-phase arrest and apoptosis in LCC2 cells.
  • In vivo, P5 significantly inhibited tumor growth in the LCC2 xenograft model with comparable efficacy to fulvestrant and a good safety profile.

Conclusions:

  • The LBP/CBS dual-targeting PROTAC strategy is effective in degrading ERα and overcoming endocrine resistance.
  • P5 represents a promising therapeutic candidate for ER-positive breast cancer resistant to endocrine therapies.
  • This approach offers a novel avenue for developing next-generation treatments for ER+ breast cancer.

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