Drug-Conjugated Tam-NHC-Gold(I) Complexes Overcome ESR1 Mutant Breast Cancer Resistance and Downregulate the RAMP3/CALCR Signaling Pathway

  • J Med Chem. 2026 Jul 23;69(14):16363-16380. doi: 10.1021/acs.jmedchem.5c02812.
Yunlong Lu  1 ,  Lijuan Liu  1 ,  Zhenlin Liang  1 ,  Wayne A Schroder  2 ,  Zhenfan Wen  1 ,  Tianpeng Zheng  1 ,  Ben Niu  3  4 ,  Chunqi Xie  3  4 ,  He Zhang  1 ,  Jian Min  5 ,  Qianming Du  3  4 ,  Wukun Liu  1
Affiliations
  • 1. School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2. School of Environment and Science, Griffith University, Nathan 4111, Australia.
  • 3. General Clinical Research Center, Nanjing First Hospital, Nanjing University of Chinese Medicine, Nanjing 210006, China.
  • 4. School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 5. School of Life Sciences, Hubei University, Wuhan 430062, China.
PMID: 42378404 DOI: 10.1021/acs.jmedchem.5c02812
Abstract

Endocrine resistance remains a major obstacle in the effective treatment of hormone-receptor-positive breast Cancer. ESR1 mutations, such as Y537S and D538G, are commonly considered to confer such resistance. It is necessary to develop novel therapeutic agents to overcome endocrine resistance. Herein, we developed drug-conjugated Tam-NHC-gold(I) complexes that can target breast Cancer cells by the binding of tamoxifen (Tam) to the G protein-coupled Estrogen receptor (GPER) present on cell membranes. The privileged complex, 7b, can significantly downregulate ER, inhibit ER downstream signaling pathways, and induce damage-associated molecular pattern (DAMP)-mediated immunogenic cell death (ICD). Mechanistically, RNA-sequencing analysis revealed that 7b can overcome mutant MCF-7Y537S resistance through the RAMP3/CALCR signaling pathway. Moreover, 7b exhibited potent antiproliferative activity on both wild-type and mutant MCF-7Y537S in xenograft mouse models with low toxicity. This study verified that 7b may offer a new approach for the treatment of endocrine-resistant breast Cancer.

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