Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer.

Endocrine resistance remains a significant problem in the clinical treatment of estrogen receptor α-positive (ERα) breast cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity. Among them, compounds and exhibited the most promising antiproliferative and ERα degradation activity in multiple ERα BC cell lines bearing either wild-type or mutant ERα. Meanwhile, compounds and disrupted the microtubule network by restraining tubulin polymerization, evidenced by inducing cell cycle arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds and remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα BC therapy, especially for the resistant variant.