Irreversible Estrogen Receptor Inhibitors

不可逆雌激素受体抑制剂

基本信息

批准号：
10507624
负责人：
Florastina L Payton-Stewart
金额：
$ 18.75万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507624
关键词：
Address Affinity Agonist Amino Acids Aromatase Inhibitors Binding Binding Proteins Biological Assay Biological Availability Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Cell Proliferation Clinic Clinical Cysteine Cytochrome P450 Development Disease Disease Progression Dose Drug Exposure Drug Kinetics Endocrine Enzymes Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Exhibits Fulvestrant Genetic Transcription Goals Growth Health In Vitro Individual Innovative Therapy Laboratories Lead Letrozole Ligand Binding Domain Mass Spectrum Analysis Measures Mediating Metabolic Metastatic breast cancer Mission Molecular Mutation Neoplasm Metastasis Oral Outcome Patients Permeability Pharmacodynamics Pharmacologic Actions Pharmacologic Substance Plasma Proteins Productivity Proteomics Public Health Raloxifene Relapse Reporter Reporting Research Resistance Selective Estrogen Receptor Modulators Somatic Mutation Structure Tamoxifen Testing Therapeutic Therapeutic Agents Thiophenes Tissues Treatment Efficacy Triphenylethylene United States National Institutes of Health Work adjuvant endocrine therapy antagonist base benzothiophene breast cancer diagnosis clinical development clinically relevant covalent bond design drug candidate hormone therapy in vivo inhibitor innovation malignant breast neoplasm mortality mutant novel patient derived xenograft model patient population preclinical efficacy preclinical study prototype receptor binding response side effect standard of care transcriptome sequencing tumor tumorigenesis

项目摘要

Project Summary Constitutively active somatic mutations in the estrogen receptor (ER) ligand binding domain (LBD) have emerged as a frequent mechanism of endocrine therapy resistance in patients with metastatic ER+ breast cancers. Unfortunately, there are no therapeutic agents to address this patient population. The long-term goal is to develop therapeutically useful irreversible ER inhibitors for the treatment of ER+ metastatic breast cancer, which will create therapy options for individuals who have failed or relapsed on current therapies. The overall objective is to identify template-based irreversible ER inhibitors that can bind to the ER with high affinity and form an irreversible covalent C-S bond with the C530 amino acid residue in the ER LBD. The central hypothesis is that a pharmaceutically optimized irreversible ER inhibitor can be obtained by incorporating clinically proven ER- binding motifs and a covalent-bond forming Michael addition moiety in the molecules. This hypothesis is supported by early triphenylethylene-based irreversible ER antagonists exhibiting uterotrophic effects similar to tamoxifen, and prototype compounds from our laboratory with thiophene (Raloxifene-like) core demonstrating lack of such effect but equally potent antagonism in the breast. The central hypothesis will be tested by pursuing three specific aims: 1) Design and synthesis of irreversible ER inhibitors; 2) Determine the impact of the irreversible ER inhibitors on proliferation in breast cancer cells, and 3) Evaluate in vivo pharmacodynamics and anti-tumor therapeutic efficacy of novel irreversible ER inhibitors. Under the first aim, irreversible ER binding inhibitors will be synthesized using cores motifs: triphenylethylenes (tamoxifen-like) and benzothiophenes (raloxifene-like) and are expected to be highly selective, potent, and to exert permanent antagonism. Under aim two, the synthesized compounds will be evaluated in their ability to form a covalent bond with ER C530 and inhibit the growth of breast cancer cells. For the third aim, the lead agent from each structural motif group will be identified for further preclinical studies and efficacy in patient-derived xenograft breast tumor models. The research here is innovative because it focuses on the use of irreversible inhibitors to overcome endocrine resistance and incorporates novel moieties to achieve high drug exposure. This contribution is significant because it will identify a class of irreversible ER inhibitors that display novel antiestrogenic effects, lacks agonist activities, and has high oral bioavailability, offering new opportunities for the development of innovative therapies to treat breast cancer.

项目摘要雌激素受体（ER）配体结合结构域（LBD）中的组成性活性体细胞突变已出现作为转移性ER+乳腺癌患者内分泌疗法耐药性的常见机制。不幸的是，没有治疗剂可以解决该患者人群。长期目标是发展治疗有用的不可逆ER抑制剂用于治疗ER+转移性乳腺癌，这将为在当前疗法上失败或复发的个人创建疗法选择。总体目标是确定基于模板的不可逆ER抑制剂，可以具有高亲和力与ER结合并形成一个 ER LBD中与C530氨基酸残基的不可逆共价C-S键。中心假设是可以通过纳入临床证明的ER-可以获得药物优化的不可逆ER抑制剂在分子中形成迈克尔添加部分的结合基序和共价键。这个假设是得到早期三苯基乙二烯的不可逆ER拮抗剂的支持，表现出类似他莫昔芬和我们实验室的原型化合物与硫芬（raloxifene）核心证明缺乏这种作用，但在乳房中同样有效的拮抗作用。中心假设将通过追求来检验三个具体目的：1）设计和合成不可逆的ER抑制剂； 2）确定不可逆的ER抑制剂对乳腺癌细胞增殖，3）评估体内药效学和新型不可逆的ER抑制剂的抗肿瘤治疗功效。在第一个目标下，不可逆转的ER具有约束力将使用核心基序合成抑制剂：三苯基乙烯（他莫昔芬）和苯甲酸苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯基苯甲酸苯基苯基苯甲酸烯和苯基苯基乙烯。（类似rAxifene），预计将具有高度选择性，有效的效果并发挥永久性拮抗作用。在目标下第二，合成化合物将以与ER C530共价键的能力进行评估抑制乳腺癌细胞的生长。对于第三个目标，每个结构基序组的主要主体将可确定用于进一步的临床前研究和在患者衍生的异种移植乳腺肿瘤模型中的功效。这这里的研究具有创新性，因为它专注于使用不可逆抑制剂克服内分泌耐药性并结合了新的部分以实现高药物暴露。这项贡献很重要，因为它将确定一类不可逆的ER抑制剂，这些抑制剂表现出新的抗雌激素作用，缺乏激动剂活动和具有高口服生物利用度，为开发创新疗法提供了新的机会来治疗乳房癌症。