Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania.
Mol Cancer Ther. 2021 Jan;20(1):11-25. doi: 10.1158/1535-7163.MCT-20-0563. Epub 2020 Nov 11.
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 (E), which are proposed as safer estrogenic agents compared with 17β-estradiol (E), for the treatment of endocrine-resistant breast cancer. TTC-352 and E are being evaluated in breast cancer clinical trials. Cell viability assays, real-time PCR, immunoblotting, 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 E, less potent full agonist E, 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 E 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 E-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.
患有长期雌激素剥夺性乳腺癌的患者，在对他莫昔芬或芳香化酶抑制剂产生耐药性后，用雌激素治疗时可出现肿瘤消退。雌激素的抗肿瘤作用归因于雌激素受体（ER）介导的细胞凋亡。雌激素治疗可能会引起不愉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的重点。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，以及天然雌激素雌三醇（E），与 17β-雌二醇（E）相比，它们被认为是更安全的雌激素药物，可用于治疗内分泌抵抗性乳腺癌。TTC-352 和 E 正在进行乳腺癌临床试验。在 11 种不同的乳腺癌模型中进行了细胞活力测定、实时 PCR、免疫印迹、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 Annexin V 染色。结果与强效全激动剂 E、弱效全激动剂 E、参比部分激动剂三苯乙烯双酚（BPTPE）和拮抗剂 4-羟基他莫昔芬和 Endoxifen 进行了比较。我们报告了 ERα 的调节和共调节剂与 SEM 和 E 的结合谱。我们描述了 TTC-352 的药理学作为一种弱的全激动剂和抗肿瘤分子机制。这项研究强调了 TTC-352 的苯并噻吩骨架，它与 Glu353 形成氢键，允许 Asp351 与 H12 相互作用，封闭 ERα 的配体结合域，募集富含 E 的共激活剂，并触发快速的 ERα 诱导未折叠蛋白反应（UPR）和细胞凋亡，这是其抗癌特性的基础。BPTPE 的酚羟基与 Thr347 形成氢键，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。
