内分泌耐药在雌激素受体α阳性 (ERα+) 乳腺癌 (BC) 的临床治疗中仍然是一个重要的问题。本研究基于一个带有硒氰 (SeCN) 侧链的桥式二环结构，开发了一系列新型双功能 ERα 降解剂。这些化合物展示了强效的 ERα 降解和微管去聚合活性。其中，35s和35t化合物在多个携带野生型或突变型 ERα 的 ERα+ BC 细胞系中表现出最有前景的抗增殖和 ERα 降解活性。同时，35s和35t化合物通过抑制微管聚合破坏了微管网络，这由35t诱导细胞周期在G2/M期停滞得到证实。在 MCF-7 和 LCC2 移植瘤模型中，35s和35t化合物显著抑制了肿瘤生长，且没有明显的毒性。最后，本研究为开发新的双靶点抗肿瘤药物候选物提供了指导，特别是针对耐药变异体的 ERα+ BC 治疗。

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.