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 35s and 35t exhibited the
most promising antiproliferative and ERα degradation activity
in multiple ERα+ BC cell lines bearing either wild-type
or mutant ERα. Meanwhile, compounds 35s and 35t disrupted the microtubule network by restraining tubulin
polymerization, evidenced by 35t inducing cell cycle
arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds 35s and 35t 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.