NCP07: A potent ERα CBS-targeted degrader with dual-action against ESR1 mutations in breast cancer
- Eur J Med Chem. 2026 Jun 30:317:119113. doi: 10.1016/j.ejmech.2026.119113.
- 1. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- 2. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
- 3. Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- 4. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
- 5. Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
- 6. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology and Biosafety, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan, 430071, China. Electronic address: [email protected].
ESR1 mutation-driven endocrine therapy (ET) resistance remains a major challenge in breast Cancer therapy. Herein, by integrating the advantages of PROTAC technology and coactivator-binding site (CBS) targeting strategy in overcoming drug resistance, we developed a class of novel and potent ERα PROTAC degraders against ET-resistant breast Cancer. Among them, compound NCP07 could potently degrade ERα and inhibited proliferation (IC50 = 0.13-1.22 μM) in both wild-type and ESR1-mutated cell lines. Mechanistic studies confirmed that compound NCP07 could not only specifically bind to CBS followed by inducing the formation of ERα-NCP07-VHL ternary complex, but also induce Apoptosis and cell cycle arrest in drug-resistant cells. Besides, compound NCP07 also exhibited favorable metabolic stability and high safety properties. Totally, the potent anti-breast Cancer activity and favorable metabolic stability of compound NCP07 not only indicated that PROTAC degrader targeting ERα CBS was an effective dual-action strategy for overcoming ESR1 mutation, but also was a promising candidate for further developing potent drugs against ET-resistant breast Cancer.