A novel ERα-targeted hydrophobic tag degrader, overcomes tamoxifen resistance via unfolded protein response-induced apoptosis and homologous recombination repair inhibition in breast cancer
- Bioorg Chem. 2026 Jun 18:180:110129. doi: 10.1016/j.bioorg.2026.110129.
- 1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Bayi Road, Wuhan 430072, China.
- 2. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
- 3. State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan 430062, China.
- 4. State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan 430062, China. Electronic address: [email protected].
- 5. Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
- 6. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Bayi Road, Wuhan 430072, China. Electronic address: [email protected].
Breast Cancer (BC), predominantly ERα-positive, often develops resistance to endocrine therapy. We designed 20a, a novel ERα Degrader based on the OBHSA scaffold with a hydrophobic amantadine tag. This compound demonstrates potent efficacy against both tamoxifen-sensitive and -resistant BC models in vitro and in vivo, with minimal systemic toxicity. Structural analysis reveals that 20a induces conformational changes in ERα (helixes 11-12), facilitating HSP70 recruitment and subsequent ubiquitin-proteasome degradation. Additionally, 20a activates the ATF4-CHOP axis of the unfolded protein response, inducing Apoptosis, while impairing homologous recombination repair through RAD51 degradation and BRCA1/2 downregulation. The latter effect creates synthetic lethality with Olaparib. Our findings elucidate the multi-mechanistic antitumor profile of 20a, highlighting its potential as a next-generation therapeutic for endocrine-resistant ERα-positive BC.