A major risk for patients having estrogen receptor α (ERα)-positive breast cancer is the recurrence of drug-resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ERα that stabilize the agonist conformation as a prominent mechanism for this acquired resistance. There are several critical gaps in our knowledge regarding the specific pharmacophore requirements of an antagonist that could effectively inhibit all or most of the different mutant ERs. To address this, we screened various chemotypes for blocking mutant ER-mediated transcriptional signaling and identified RU58668 as a model compound that contains structural elements that support potent ligand-induced inhibition of mutant ERs. We designed and synthesized a focused library of novel antagonists and probed how small and large perturbations in different ligand structural regions influenced inhibitory activity on individual mutant ERs in breast cancer cells. Effective inhibition derives from both nonpolar and moderately polar motifs in a multifunctional side chain of the antagonists, with the nature of the ligand core making important contributions by increasing the potency of ligands possessing similar types of side chains. Some of our new antagonists potently blocked the transcriptional activity of the three most common mutant ERs (L536R, Y537S, D538G) and inhibited mutant ER-mediated cell proliferation. Supported by our molecular modeling, these studies provide new insights into the role of specific components, involving both the ligand core and multifunctional side chain, in suppressing wild-type and mutant ER-mediated transcription and breast cancer cell proliferation.

中文翻译：

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组成型活性突变雌激素受体的拮抗剂：深入了解抗雌激素核心和侧链的作用。

雌激素受体α（ERα）阳性乳腺癌患者的一个主要风险是在内分泌治疗初始成功治疗后耐药转移的复发。最近的研究表明 ERα 配体结合域中的许多激活突变使激动剂构象稳定，这是这种获得性耐药的主要机制。关于拮抗剂的特定药效团要求，我们的知识存在几个关键空白，该拮抗剂可以有效抑制所有或大部分不同的突变 ER。为了解决这个问题，我们筛选了用于阻断突变 ER 介导的转录信号传导的各种化学类型，并将 RU58668 确定为一种模型化合物，它包含支持有效配体诱导的突变 ER 抑制的结构元件。我们设计并合成了一个集中的新型拮抗剂库，并探讨了不同配体结构区域的大小扰动如何影响对乳腺癌细胞中单个突变 ER 的抑制活性。有效抑制来自拮抗剂多功能侧链中的非极性和中等极性基序，配体核心的性质通过增加具有相似类型侧链的配体的效力做出重要贡献。我们的一些新拮抗剂有效阻断了三种最常见的突变 ER（L536R、Y537S、D538G）的转录活性，并抑制了突变 ER 介导的细胞增殖。在我们的分子模型的支持下，这些研究为特定成分的作用提供了新的见解，