Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. In the present study, series of novel 6-OH-benzothiophene (BT) derivatives targeting ERα and deriving from Raloxifene were designed, synthesized, and biologically evaluated as covalent antagonists. Driven by the antiproliferative efficacy in ER+ breast cancer cells, our chemical optimization finally led to compound 19d that with potent antagonistic activity in ER+ tumor cells while without agonistic activity in endometrial cells. Moreover, the docking simulation was carried out to elucidate the binding mode, revealing 19d as an antagonist and covalently binding to the cysteine residue at the 530 position of ER helix H11.

几十年来，雌激素受体 α 一直是乳腺癌的有效治疗靶点。然而，大约 50% 最初对标准护理 (SoC) 有反应的患者，例如接受他莫昔芬治疗，通常不可避免地会发展为内分泌抗性 ER+ 表型。最近，靶向 ERα 的选择性雌激素受体共价拮抗剂 (SERCA) 已被证明是一种治疗选择。在本研究中，一系列新型 6-OH-苯并噻吩 (BT) 衍生物靶向 ERα 并衍生自雷洛昔芬，被设计、合成和生物学评估为共价拮抗剂。在 ER+ 乳腺癌细胞的抗增殖功效的推动下，我们的化学优化最终导致化合物19d在 ER+ 肿瘤细胞中具有强效拮抗活性，而在子宫内膜细胞中没有激动活性。此外，进行对接模拟以阐明结合模式，揭示19d作为拮抗剂并与ER螺旋H11的530位的半胱氨酸残基共价结合。