Patients with long-term estrogen-deprived breast cancer, after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen's antitumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecologic and nongynecologic adverse events; thus, the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEM) BMI-135 and TTC-352, and the naturally occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared with 17β-estradiol (E2), for the treatment of endocrine-resistant breast cancer. TTC-352 and E4 are being evaluated in breast cancer clinical trials. Cell viability assays, real-time PCR, immunoblotting, ERE DNA pulldowns, mass spectrometry, X-ray crystallography, docking and molecular dynamic simulations, live cell imaging, and Annexin V staining were conducted in 11 biologically different breast cancer models. Results were compared with the potent full agonist E2, less potent full agonist E4, the benchmark partial agonist triphenylethylene bisphenol (BPTPE), and antagonists 4-hydroxytamoxifen and endoxifen. We report ERα's regulation and coregulators’ binding profiles with SEMs and E4. We describe TTC-352′s pharmacology as a weak full agonist and antitumor molecular mechanisms. This study highlights TTC-352′s benzothiophene scaffold that yields an H-bond with Glu353, which allows Asp351-to-helix 12 (H12) interaction, sealing ERα's ligand-binding domain, recruiting E2-enriched coactivators, and triggering rapid ERα-induced unfolded protein response (UPR) and apoptosis, as the basis of its anticancer properties. BPTPE's phenolic OH yields an H-Bond with Thr347, which disrupts Asp351-to-H12 interaction, delaying UPR and apoptosis and increasing clonal evolution risk.

中文翻译：

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雌激素模拟 TTC-352 快速诱导未折叠蛋白反应和细胞凋亡用于治疗内分泌耐药性乳腺癌

长期缺乏雌激素的乳腺癌患者，在对他莫昔芬或芳香酶抑制剂产生耐药性后，在接受雌激素治疗后会出现肿瘤消退。雌激素的抗肿瘤作用归因于通过雌激素受体 (ER) 的细胞凋亡。雌激素治疗可能会产生令人不快的妇科和非妇科不良事件；因此，开发更安全的雌激素药物仍然是临床优先事项。在这里，我们研究了合成的选择性雌激素模拟物 (SEM) BMI-135 和 TTC-352，以及天然存在的雌激素雌四醇 (E4)，与 17β-雌二醇 (E2) 相比，它们被认为是更安全的雌激素药物，用于治疗内分泌- 耐药性乳腺癌。TTC-352 和 E4 正在乳腺癌临床试验中进行评估。细胞活力测定、实时 PCR、免疫印迹、ERE DNA pulldowns、质谱、X 射线晶体学、对接和分子动力学模拟、活细胞成像和膜联蛋白 V 染色在 11 个生物学不同的乳腺癌模型中进行。将结果与强效完全激动剂 E2、效力较低的完全激动剂 E4、基准部分激动剂三苯乙撑双酚 (BPTPE) 以及拮抗剂 4-羟基三苯氧胺和内昔芬进行了比较。我们用 SEM 和 E4 报告 ERα 的调节和辅助调节剂的结合谱。我们将 TTC-352 的药理学描述为弱全激动剂和抗肿瘤分子机制。这项研究突出了 TTC-352 的苯并噻吩支架，它与 Glu353 产生 H 键，允许 Asp351 与螺旋 12 (H12) 相互作用，密封 ERα 的配体结合域，招募富含 E2 的共激活剂，并触发快速 ERα 诱导的未折叠蛋白反应 (UPR) 和细胞凋亡，这是其抗癌特性的基础。BPTPE 的酚羟基产生与 Thr347 的 H 键，破坏 Asp351 与 H12 的相互作用，延迟 UPR 和细胞凋亡并增加克隆进化风险。