Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands

项目总结 激素疗法在雌激素受体阳性妇女的治疗中具有革命性意义 (Er+)乳腺癌，大大提高了存活率。针对ER的激素疗法包括选择性 雌激素受体调节剂SERM，如他莫昔芬和选择性雌激素受体下调调节剂 (SERDS)，如弗维斯特，而芳香酶抑制剂阻止雌激素的生物合成。这些 治疗方法有显著的副作用，长期使用可能会导致大约1-1的化疗耐药- 三分之一的接受治疗的妇女，往往会导致更具侵袭性的癌症。此外，他莫昔芬的使用是 与子宫内膜增厚和增生、息肉和癌症的发生率增加有关。近期 研究已经确定了涉及跨越G蛋白偶联受体的7-跨膜的新途径 接受SERM/SERD治疗的患者的GPER。GPER的交叉反应性药理兴奋性 有助于激素抵抗和子宫的非靶点效应，因为所有临床批准的抗- 雌激素作为GPER的激动剂，刺激这些途径。ER/GPER的这一关键问题 SERM和SERD药物的开发没有涉及选择性问题。在我们之前的工作中，我们 发现并表征了不与ERα或ERβ结合的新型选择性GPER配体。最近，我们 发现了一种新的小分子，可以在不受GPER干扰的情况下首次靶向ER。 由于目前的抗雌激素药物不区分ERα/β和GPER，我们新发现的小 分子提供了创造新的配体和治疗药物来选择性靶向ERα的机会。 通过对这种第一代ER-α选择性化合物进行化学修饰，我们改进了 亲和力、受体选择性和拮抗剂/激动剂图谱，最终目标是创建真正的ERα- 选择性的拮抗剂。本方案的具体目的是：1.合成和拆分生物活性物质 优化的ER-α靶向AB-SERD化合物的手性；2.优先排序 通过受体结合、细胞信号传递、增殖和毒性等体外方法合成化合物 3.体内测定铅化合物的抗肿瘤和ADMET性质，使用ER依赖和 抗激素抗性转基因、异种移植和PDX肿瘤。 这些研究的成功完成将确定创新的对映专一性化合物为 独特的药理学工具，用于描述ER和GPER的单独功能，并启动 开发一流的治疗药物，目标是减少抗激素耐药复发 乳腺癌，每年提高20多万妇女的存活率和生活质量 被诊断为ER阳性乳腺癌。

PROJECT SUMMARY Hormonal therapies have been revolutionary in the treatment of women with estrogen receptor positive (ER+) breast cancers, greatly enhancing survival. ER-targeted hormonal therapies include selective estrogen receptor modulators SERMs, such as tamoxifen, and selective estrogen receptor downregulators (SERDs), such as fulvestrant, whereas aromatase inhibitors block the biosynthesis of estrogen. These therapies have significant side effects, and their prolonged use can lead to chemoresistance in about one- third of treated women, often resulting in more aggressive cancers. Furthermore, tamoxifen use is associated with increased incidence of endometrial thickening and hyperplasia, polyps and cancer. Recent studies have identified novel pathways involving the 7-transmembrane spanning G protein-coupled receptor GPER in patients undergoing SERM/SERD therapies. Cross-reactive pharmacological agonism of GPER contributes to both hormonal resistance and off-target effects in the uterus as all clinically approved anti- estrogens act as agonists for GPER and stimulate these pathways. This critical issue of ER/GPER selectivity has not been addressed in the development of SERM and SERD drugs. In our previous work, we discovered and characterized novel selective ligands for GPER that do not bind ERα or ERβ.Recently, we discovered a novel small molecule that for the very first-time targets ER without interference of GPER. As current anti-estrogens do not discriminate between ERα/β and GPER, our newly identified small molecule affords the opportunity to create novel ligands and therapeutic agents to selectively target ERα. Through chemical modifications to this first-generation ERα-selective compound, we have improved the affinity, receptor-selectivity and antagonist/agonist profile with the ultimate goal of creating truly ERα- selective antagonists. The specific aims of this proposal are to: 1. Synthesize and resolve the bioactive enantiomer of optimized ERα-targeted AB-SERD compounds with GPER anti-selectivity; 2. Prioritize compounds through in vitro methods including receptor binding, cell signaling, proliferation and toxicity and 3. Determine in vivo anti-tumor and ADMET properties of lead compounds, employing ER-dependent and anti-hormone-resistant transgenic, xenograft and PDX tumors. The successful completion of these studies will identify innovative enantiospecific compounds as unique pharmacological tools for delineating the individual functions of ER and GPER, and also initiating the development of first-in-class therapeutic agents, with the goal of reducing anti-hormone resistant recurrence of breast cancer, enhancing survival and the quality of life for the greater than 200,000 women annually diagnosed with ER-positive breast cancer.