A novel ERα-targeted hydrophobic tag degrader, overcomes tamoxifen resistance via unfolded protein response-induced apoptosis and homologous recombination repair inhibition in breast cancer.

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.