雌激素受体α(ERα)是一个配体依赖的主要转录调节因子和乳腺癌病理的关键驱动因素。小分子激素和竞争性拮抗剂偏爱独特的ERα构象组合，在乳腺癌和其他激素反应性组织中引发特定的配体特异性转录程序。通过影响不同的配体结合区域结构特征，非传统配体支架可以重定向ERα基因组结合模式，参与新的治疗转录程序。为了改善我们对这些ERα结构-转录关系的理解，我们开发了一系列基于抗雌激素elacestrant和lasofoxifene的化学非常规拮抗剂。高分辨率的x射线共晶结构显示这些分子影响ERα配体结合口袋中的经典和独特结构莫蒂夫。它们在ERα基因组活性上表现出中等的拮抗效力，但对弥漫性乳腺癌细胞具有有效的抗增生作用。有趣的是，它们偏好于乳腺癌细胞中的4-羟基他莫昔芬样地积累ERα，但在子宫内膜细胞系中缺乏子宫病变活性。重要的是，RNA测序表明，这些引领分子参与的转录途径与选择性雌激素受体降解剂fulvestrant相似。这一进展表明，可以在不影响乳腺癌细胞中ERα积累的情况下实现fulvestrant样的基因组活性。 ©2022年。作者(们)。

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.© 2022. The Author(s).