Discovery of Effective Dual PROTAC Degraders with Synergistic Antitumor Activity for Overcoming Tamoxifen-Resistant Breast Cancer.

Endocrine therapies for estrogen receptor-positive (ER+) breast cancer (BC) often encounter primary or acquired resistance, and elevated expression of histone deacetylase 6 (HDAC6) exacerbates therapeutic challenges. Emerging evidence indicates that simultaneous attenuation of estrogen receptor α (ERα) and HDAC6 activities represents a promising strategy to overcome endocrine resistance. Herein, we report a novel hybrid ERα/HDAC6 dual-targeting PROTAC V-12c, which selectively degraded ERα and HDAC6 in vitro and in vivo and exhibited superior antiproliferation efficacy across a panel of BC cell lines. Mechanistically, V-12c degraded both ERα and HDAC6 via the proteasome pathway, induced cell cycle arrest and apoptosis, attenuated hormonal response, disrupted the autophagy-lysosome function, and triggered ferroptosis, collectively contributing to overcoming tamoxifen resistance. Importantly, V-12c potently suppressed tumor growth in endocrine-resistant BC models, outperforming single-target therapies. This study identified a multimechanistic action of dual PROTAC V-12c with potent antitumor effects, providing a promising therapeutic strategy for endocrine-resistant BC.