Drug-Conjugated Tam-NHC-Gold(I) Complexes Overcome ESR1 Mutant Breast Cancer Resistance and Downregulate the
Yunlong Lu1, Lijuan Liu1, Zhenlin Liang1
1School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Journal of Medicinal Chemistry
|June 30, 2026
Summary
A novel gold(I) complex, 7b, targets endocrine-resistant breast cancer by downregulating estrogen receptor (ER) and inducing immunogenic cell death (ICD). This compound shows promise in preclinical models, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Medicinal Chemistry
- Cancer Immunology
Background:
- Endocrine resistance, often driven by ESR1 mutations (e.g., Y537S), hinders effective treatment for hormone-receptor-positive breast cancer.
- Developing novel agents to overcome endocrine resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To design and evaluate novel drug-conjugated Tam-NHC-gold(I) complexes targeting breast cancer cells.
- To investigate the efficacy of complex 7b in overcoming endocrine resistance and inducing immunogenic cell death (ICD).
Main Methods:
- Synthesis and characterization of Tam-NHC-gold(I) complexes.
- Assessment of complex 7b's ability to downregulate estrogen receptor (ER) and inhibit downstream signaling.
- RNA-sequencing analysis to elucidate the mechanism of action against mutant MCF-7Y537S cells.
- Evaluation of antiproliferative activity and toxicity in xenograft mouse models.
Main Results:
- Complex 7b effectively targets breast cancer cells via tamoxifen (Tam) binding to G protein-coupled estrogen receptor (GPER).
- 7b significantly downregulates ER, inhibits ER signaling, and induces damage-associated molecular pattern (DAMP)-mediated immunogenic cell death (ICD).
- RNA-sequencing identified the RAMP3/CALCR pathway as key to overcoming MCF-7Y537S resistance.
- 7b demonstrated potent antiproliferative activity against wild-type and mutant MCF-7Y537S in vivo with low toxicity.
Conclusions:
- Complex 7b represents a promising therapeutic strategy for endocrine-resistant breast cancer.
- The RAMP3/CALCR pathway is a potential target for overcoming resistance mediated by ESR1 mutations.
- Drug-conjugated gold(I) complexes offer a novel approach for treating resistant breast cancer phenotypes.
Related Concept Videos
02:57Targeted Cancer Therapies
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
There are several types of targeted therapies against specific...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...