Human Oncology and Pathogenesis Program , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
The Ben May Department for Cancer Research , University of Chicago , Chicago , Illinois 60637 , United States.
ACS Chem Biol. 2018 Dec 21;13(12):3374-3384. doi: 10.1021/acschembio.8b00877. Epub 2018 Nov 26.
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.
对于患有雌激素受体 α（ERα）阳性乳腺癌的患者来说，一个主要的风险是在最初成功接受内分泌治疗后，耐药性转移的复发。最近的研究表明，配体结合域中的许多激活突变使 ERα 稳定在激动剂构象中，这是获得性耐药的一个重要机制。我们对拮抗剂的特定药效团要求知之甚少，这些拮抗剂可以有效地抑制所有或大多数不同的突变型 ER。为了解决这个问题，我们筛选了各种化学型以阻断突变型 ER 介导的转录信号，并确定 RU58668 为一种模型化合物，它包含支持突变型 ER 有效配体诱导抑制的结构元素。我们设计并合成了一种新型拮抗剂的聚焦文库，并研究了不同配体结构区域的小和大扰动如何影响乳腺癌细胞中单个突变型 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类似侧链类型的配体的效力来做出重要贡献。我们的一些新拮抗剂能有效地阻断三种最常见的突变型 ER（L536R、Y537S、D538G）的转录活性，并抑制突变型 ER 介导的细胞增殖。这些研究得到我们的分子建模支持，为了解特定成分（包括配体核心和多功能侧链）在抑制野生型和突变型 ER 介导的转录和乳腺癌细胞增殖中的作用提供了新的见解。
