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Updated: Aug 27, 2025
Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen
Guillem Loren1, Irene Espuny1, Alicia Llorente1
1Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.
Abstract:
In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitive inhibitor of oestrogen, has played a major role in therapeutics. However, primary and acquired resistance to hormone blockade occurs in a large subset of these cancers, and new approaches are urgently needed. Aromatase inhibitors and receptor degraders were approved and alternatively used. Yet, resistance appears in the metastatic setting. Here we report the design and synthesis of a series of proteolysis targeting chimeras (PROTACs) that induce the degradation of estrogen receptor alpha in breast cancer MCF-7 (ER+) cells at nanomolar concentration. Using a warhead based on 4-hydroxytamoxifen, bifunctional degraders recruiting either cereblon or the Von Hippel Lindau E3 ligases were synthesized. Our efforts resulted in the discovery of TVHL-1, a potent ERα degrader (DC50: 4.5 nM) that we envisage as a useful tool for biological study and a platform for potential therapeutics.
Insights
Researchers developed novel PROTACs to degrade estrogen receptor alpha (ERα) in ER+ breast cancer. One compound, TVHL-1, shows potent ERα degradation, offering a potential new therapeutic strategy for hormone-resistant breast cancer.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Estrogen receptor-positive (ER+) breast cancer treatment has historically targeted the estrogenic receptor signaling pathway.
- Tamoxifen and aromatase inhibitors are common therapies, but resistance frequently develops, necessitating new treatment strategies.
- Existing therapies face challenges with primary and acquired resistance, particularly in the metastatic setting.
Purpose of the Study:
- To design and synthesize novel proteolysis targeting chimeras (PROTACs) capable of degrading estrogen receptor alpha (ERα).
- To evaluate the efficacy of these PROTACs in ER+ breast cancer cells.
- To identify a potent ERα degrader for potential therapeutic applications and biological studies.
Main Methods:
- Synthesis of bifunctional PROTACs utilizing a 4-hydroxytamoxifen warhead.
- PROTACs were designed to recruit either the cereblon (CRBN) or Von Hippel-Lindau (VHL) E3 ligases.
- Evaluation of ERα degradation in MCF-7 (ER+) breast cancer cells at nanomolar concentrations.
Main Results:
- Successfully designed and synthesized a series of PROTACs targeting ERα.
- Demonstrated that these PROTACs induce ERα degradation in ER+ breast cancer cells.
- Identified TVHL-1 as a potent ERα degrader with a DC50 of 4.5 nM.
Conclusions:
- The developed PROTACs effectively degrade ERα in breast cancer cells.
- TVHL-1 represents a promising ERα degrader with potential as a research tool and therapeutic candidate.
- This approach offers a new avenue for overcoming resistance in ER+ breast cancer treatment.
