乳腺癌（BC）是一种高度异质性肿瘤，已超过肺癌成为女性最常诊断的癌症。在临床实践中，治疗雌激素受体α (ERα) 阳性 BC 的主要方法是通过内分泌治疗，其中涉及使用他莫昔芬和氟维司群等靶向 ERα 的药物。然而，新发耐药或获得性耐药的问题提出了重大的临床挑战，强调了开发新治疗策略的迫切需要。对此，我们成功设计并开发了一种新型选择性雌激素受体降解剂（SERD），称为OBHSA，它特异性靶向并降解ERα，显示出显着的功效。我们的研究结果揭示了 OBHSA 在抑制各种 BC 细胞（包括他莫昔芬敏感和他莫昔芬耐药 BC 细胞）增殖方面的有效性，表明其克服内分泌耐药性的巨大潜力。在机制方面，我们发现 OBHSA 通过两种不同的途径克服了他莫昔芬耐药性。首先，OBHSA 以 ERα 依赖性方式降解细胞周期蛋白 D1，从而阻断细胞周期。其次，OBHSA 诱导细胞内活性氧含量升高，引发未折叠蛋白反应 (UPR) 的过度激活，最终导致细胞凋亡。总之，我们的发现证明 OBHSA 通过诱导细胞周期停滞和 UPR 介导的细胞凋亡来发挥抗肿瘤作用。这些发现为开发针对内分泌耐药 BC 的新型治疗药物带来了希望。版权所有 © 2024。由 Elsevier Ltd 出版。

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.Copyright © 2024. Published by Elsevier Ltd.