Targeting mutant estrogen receptor driven breast cancers

靶向突变雌激素受体驱动的乳腺癌

基本信息

批准号：
10255559
负责人：
Sharron Gargosky
金额：
$ 98.21万
依托单位：
ETIRARX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255559
关键词：
Animal Model Animals Apoptotic Benzamides Binding Bioavailable Biodistribution Biological Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Canis familiaris Cardiovascular system Cell Death Cell Line Clinical Clinical Trials Detection Dose Drug Design Drug Kinetics Drug Targeting ESR1 gene Endocrine Endoplasmic Reticulum Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Fulvestrant Funding Genetic Genetic Transcription Grant Growth In Vitro Intellectual Property Lead Legal patent Ligand Binding Domain Malignant Neoplasms Maximum Tolerated Dose Mediating Metastatic breast cancer Modeling Molecular Mutation Natural Killer Cells Neoplasm Metastasis Normal Cell Oral Oral Administration Outcome Patients Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Pre-Clinical Model Primary Neoplasm Production Progression-Free Survivals Property Protein Biosynthesis Proteins Rattus Recovery Recovery of Function Refractory Resistance Safety Small Business Innovation Research Grant Structure Testing Tissues Toxic effect Translating Woman Work Xenograft Model Xenograft procedure analog cell growth clinical efficacy clinical translation clinically relevant design efficacy testing efficacy validation endoplasmic reticulum stress first-in-human genetically modified cells hormone therapy in vivo knock-down lead candidate malignant breast neoplasm meetings molecular modeling mutant nonsynonymous mutation novel patient derived xenograft model pre-clinical preclinical study programs respiratory response small molecule targeted treatment therapeutically effective therapy design therapy resistant transcriptome tumor

项目摘要

Project Summary/Abstract A majority of Breast cancers (BC) express estrogen receptor alpha (ERα). While endocrine therapies targeting either estrogen production or ERα are effective, acquired resistance is common. Sequencing of metastatic endocrine therapy-resistant (ETR) tumors has shwown that ERα mutations are frequent (30-40%), do not respond to endocrine therapies and are the molecular drivers of ETR-BC. Thus, drugs designed to specifically target these ERα mutations in ETR-BC represent a significant unmet clinical need. We leveraged the recent structural characterization of the mutant ERα ligand binding domain (LBD) to rationally design bis-benzamides to fit the binding pocket. Following iterative rounds of modeling, synthesis, testing and optimization with >2000 bis-benzamides, we have identified a lead compound, ERX-315, that binds more avidly to ERα LBD. Our preliminary studies showed that ERX-315 has potent anti-proliferative activity against mutant ERα-driven tumors, as seen in genetically modified cell lines in vitro, patient derived explants (PDEs) ex vivo and patient derived xenografts (PDXs) in vivo. Importantly, a methylated version of ERX-315, ERX-314 binds the mutant ERα poorly and does not affect proliferation of these tumors. Ultrastructural and molecular studies reveal that ERX-315, but not ERX-314 (a methylated version of ERX-315, does not bind ERα, serves as a negative control) induces significant endoplasmic reticulum stress, leading to a shutdown of de novo protein synthesis and apoptotic cell death in BC. Importantly, ERX-315 does not induce endoplasmic reticulum stress or cell death in normal cells and is non-toxic in animal models. We have shown that this capacity of ERX- 315 to induce endoplasmic reticulum stress is unique among drugs targeting ERα, including selective ERα modulators and degraders, such as GDC-0180, AXD-9496 and fulvestrant. The objective of this direct Phase II SBIR proposal is to enable EtiraRx to perform IND-enabling studies for clinical translation of ERX-315 in ETR-BCs. We have shown that ERX-315 has favorable pharmacologic parameters for clinical translation and is amenable to good manufacturing practice manufacturing. In Aim 1, we will we will perform dose-ranging finding studies in two species and define maximum tolerated dose and toxicity at that dose. In Aim2, we will synthesize large-scale batches of ERX-315 and will perform single- and multi-dose pharmacokinetic studies and evaluate tissue biodistribution. We will define 30-day toxicity in rats and dogs with a 2-week recovery, and evaluate functional recovery, cardiovascular and respiratory safety. In Aim 3, We will test the efficacy of clinical grade ERX-315 in biologically and clinically relevant preclinical models of ETR-BC, including patient derived xenografts and patient derived explants. The intellectual property around ERX-315 is protected by multiple patents licensed to EtiraRx. a novel small molecule targeting mutant ERα, and with an unique ability to induce endoplasmic reticulum stress and apoptotic cell death. If successful, our proposed studies will enable within 2 years the first-in-class studies with ERX-315 in women with ETR-BC.

项目概要/摘要大多数乳腺癌（BC）在内分泌治疗时表达雌激素受体α（ERα）。靶向雌激素产生或 ERα 是有效的，获得性耐药很常见。转移性内分泌治疗耐药 (ETR) 肿瘤已表明 ERα 突变很频繁 (30-40%)，对内分泌治疗没有反应，并且是 ETR-BC 的分子驱动因素，因此，药物设计用于治疗 ETR-BC。专门针对 ETR-BC 中的这些 ERα 突变代表了一个重大的未满足的临床需求。我们利用突变 ERα 配体结合域 (LBD) 的最新结构特征来经过几轮迭代的建模、合成、合理设计双苯甲酰胺以适应结合口袋。通过对超过 2000 种双苯甲酰胺进行测试和优化，我们确定了一种先导化合物 ERX-315，它可以结合我们的初步研究表明 ERX-315 具有有效的抗增殖活性。对抗突变 ERα 驱动的肿瘤，如体外转基因细胞系、患者来源的外植体中所见 (PDE) 体外和患者体内异种移植物 (PDX) 重要的是，ERX-315 的甲基化版本， ERX-314 与突变 ERα 的结合效果较差，并且不影响这些肿瘤的增殖。分子研究表明，ERX-315，而不是 ERX-314（ERX-315 的甲基化版本）不结合 ERα，作为阴性对照）诱导显着的内质网应激，导致从头关闭 BC 中的蛋白质合成和细胞凋亡重要的是，ERX-315 不会诱导内质网。正常细胞中的应激或细胞死亡，并且在动物模型中是无毒的，我们已经证明 ERX- 的这种能力。 315 诱导内质网应激的作用在针对 ERα（包括选择性 ERα）的药物中是独一无二的调节剂和降解剂，例如 GDC-0180、AXD-9496 和氟维司群。该直接 II 期 SBIR 提案的目标是使 EtiraRx 能够进行 IND 支持研究 ERX-315 在 ETR-BC 中的临床转化我们已经证明 ERX-315 具有良好的药理学作用。临床转化参数，并符合良好生产规范制造在目标 1 中，我们。我们将在两个物种中进行剂量范围发现研究并确定最大耐受剂量和毒性在 Aim2 中，我们将大规模合成 ERX-315，并将进行单剂量和多剂量。我们将定义大鼠和狗的药代动力学研究并评估组织生物分布。为期 2 周的恢复，并评估功能恢复、心血管和呼吸安全。在目标 3 中，我们将进行评估。测试临床级 ERX-315 在生物学和临床相关的 ETR-BC 临床前模型中的功效，包括患者来源的异种移植物和患者来源的外植体。ERX-315 的知识产权是。受到授予 EtiraRx 的多项专利保护，这是一种针对突变 ERα 的新型小分子，并且具有诱导内质网应激和细胞凋亡的独特能力如果成功，我们建议。研究将在 2 年内对 ETR-BC 女性进行 ERX-315 的一流研究。