Developing an Orally Bioavailable SERD for Treatment of Metastatic/Advanced Breast Cancer

项目摘要 选择性雌激素受体下调调节剂(SERDS)是一类内分泌治疗药物 它们既是雌激素受体(ER)拮抗剂，又是ER降解剂，有效地治疗 转移性或晚期乳腺癌，对非裔美国女性的影响不成比例。 FULVESTRANT是FDA批准的唯一一种用于晚期或转移性乳腺癌的SERD 作为一线和二线内分泌剂。然而，这种注射用药效果很差。 生物利用度，需要30天才能达到其最大稳态血浆浓度， 在激素抵抗环境下，将临床应答率限制在20%以下。口述 更多的药物暴露和更快的行动将带来直接的临床好处 晚期乳腺癌患者。此外，鉴于FDA最近批准了Fulvestrant 作为CDK4/6抑制剂帕博西利的联合治疗晚期乳腺癌， 口服SERD在联合治疗环境中的临床应用也非常重要。 口腔SERDS的研究进展仅限于非甾体分子，有几个 目前正在进行第一阶段的临床试验，但没有一项进展到第二阶段临床 审判。我们的先导化合物ZB716在生物利用度方面显示了良好的临床前数据， 药效和毒理学。ZB716与ER高亲和力结合发挥其抗雌激素作用 在表达雌激素受体的乳腺癌细胞上。他莫昔芬幼稚和对他莫昔芬耐药的乳房 癌细胞，ZB716有效地抑制细胞增殖并有效地降解激素 受体的作用呈剂量依赖关系。在动物身上，我们已经证明了ZB716的优势 口服生物利用度与富维司琼相比。而且，在直接比较两个口头 SERDS临床试验中，ZB716是一种更强的抗雌激素和ER降解剂。为了进一步 促进ZB716的临床前开发我们建议研究ZB716的体内疗效 ZB716在内分泌抵抗的患者来源的乳腺肿瘤模型中最接近 显示为SERD的临床环境。我们还将评估ZB716的疗效 与CDK4/6抑制剂Palbociclib结合，并探讨其作用机制 ZB716在表达突变型ER的患者来源的异种移植(PDX)上的表达 ZB716与突变型内质网的结合行为及其对内质网α-辅调节因子相互作用的调控 最后确定了制备ZB716的最佳反应条件 更大规模，调查其物理性质和毒理学研究的配方选择 在动物身上，并进行代谢概况、药代动力学和生物利用度研究。 完成拟议的研究将提供关键的疗效数据，以确定ZB716 对治疗内分泌耐药、ESR1突变的乳腺癌是否有效 通过内质网起作用的抗雌激素和雌激素受体降解。这些研究还将证明 ZB716与CDK4/6抑制剂联合应用的临床应用此外， 合成方法的优化将为原料药的规模化制造和安全性铺平道路 药理学和物理化学特性将满足IND使能数据。总而言之， 拟议的研究将使这种前景看好的口服SERD进入临床试验，以测试其安全性 以及对乳腺癌患者的疗效。

Project Summary Selective estrogen receptor downregulators (SERDs) are a class of endocrine therapy agents that act both as estrogen receptor (ER) antagonists and ER degraders effective in treating metastatic or advanced breast cancer that disproportionately affects African American women. Fulvestrant is the only FDA approved SERD indicated for advanced or metastatic breast cancer both as a first line and second line endocrine agent. However, this injection only drug is poorly bioavailable and it takes 30 days to reach its maximal steady-state plasma concentration, limiting the clinical response rate to lower than 20% in the hormone resistant setting. An oral SERD with greater drug exposure and faster action would bring immediate clinical benefits to patients with advanced breast cancer. Further, in light of the recent FDA approval of fulvestrant as a combination therapy with CDK4/6 inhibitor palbociclib for advanced breast cancer, the clinical utility of an oral SERD in the combination treatment setting is also very significant. Advances in oral SERDs development have been limited to nonsteroidal molecules with several being currently evaluated in phase 1 clinical trials, yet none has advanced to phase II clinical trials. Our lead compound, ZB716, has shown promising preclinical data in bioavailability, efficacy, and toxicology. ZB716 binds to ER with high affinity and exerts its antiestrogenic effect on ER-expressing breast cancer cells. In both tamoxifen naive and tamoxifen resistant breast cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose-dependent manner. In animals, we have shown that ZB716 has far superior oral bioavailability when compared to fulvestrant. Moreover, in direct comparison to the two oral SERDs under clinical trials, ZB716 is a stronger antiestrogen and ER-degrader. To further advance the preclinical development of ZB716 we propose to investigate the in vivo efficacy of ZB716 in endocrine resistant, patient derived breast tumor models that most closely resemble clinical settings for which SERD is indicated. We will also evaluate ZB716 efficacy in combination with a CDK4/6 inhibitor, palbociclib and investigate the mechanism of action of ZB716 on patient-derived xenografts (PDX) expressing mutant forms of ER and determine the binding behavior of ZB716 to mutant ERs and its modulation of ERα-coregulator interactions. Finally, we will determine optimal reaction conditions under which ZB716 can be prepared in larger scale, investigate its physical properties and formulation options for toxicological studies in animals, and conduct metabolic profiling, pharmacokinetics, and bioavailability studies. Accomplishing the proposed studies will provide key efficacy data to determine whether ZB716 is effective in treating endocrine resistant, ESR1 mutant breast cancer and whether it is a true antiestrogen and ER degrader by acting through the ER. The studies will also demonstrate the clinical utility of ZB716 as a combination therapy when used with a CDK4/6 inhibitor. Moreover, synthetic method optimization will pave the way for scalable manufacture of the API, and safety pharmacology and physical chemical properties will fulfill IND-enabling data. In summary, the proposed research will advance this promising oral SERD towards clinical trials to test its safety and efficacy in breast cancer patients.