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SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer
Yunlong Lu1, Xinyu Sheng1, Chao Liu2
1Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Abstract:
The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.
Insights
This study introduces dual-targeting complexes combining a selective estrogen receptor degrader (SERD) with a thioredoxin reductase (TrxR) inhibitor for ER-positive breast cancer. Complex 23 effectively inhibits cancer growth and induces immunogenic cell death via ROS signaling.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Selective estrogen receptor degraders (SERDs) offer novel therapeutic strategies for ER-positive advanced breast cancer.
- Thioredoxin reductase (TrxR) is a key regulator of cellular redox balance and a potential anticancer target.
- Combination therapies are being explored to enhance efficacy and overcome resistance in breast cancer treatment.
Purpose of the Study:
- To develop novel dual-targeting complexes combining a SERD candidate (G1T48) with an N-heterocyclic carbene gold(I) [NHC-Au(I)] TrxR inhibitor.
- To investigate the antiproliferative activity and mechanism of action of these dual-targeting complexes in ER-positive breast cancer.
- To elucidate the role of the ER/TrxR-ROS-immunogenic cell death (ICD) axis in breast cancer.
Main Methods:
- Synthesis and characterization of dual-targeting complexes integrating a SERD and a TrxR inhibitor.
- In vitro evaluation of antiproliferative activity against ER-positive breast cancer cell lines (e.g., MCF-7).
- Assessment of ER degradation, TrxR inhibition, reactive oxygen species (ROS) generation, and induction of ICD.
- In vivo efficacy study using a xenograft mouse model.
Main Results:
- Complex 23 demonstrated significant antiproliferative effects by simultaneously degrading ER and inhibiting TrxR activity.
- The compound induced immunogenic cell death (ICD) in cancer cells, mediated by ROS production.
- The ER/TrxR-ROS-ICD axis was identified as a critical pathway in ER-positive breast cancer.
- In vivo studies confirmed the potent antitumor activity of complex 23 in a mouse model.
Conclusions:
- Dual-targeting complexes offer a promising strategy for treating ER-positive advanced breast cancer.
- Complex 23 represents a novel therapeutic agent with a multi-pronged mechanism of action, including ER degradation, TrxR inhibition, and ROS-mediated ICD.
- This research opens new avenues for drug development targeting the identified ER/TrxR-ROS-ICD axis.
