Irreversible Estrogen Receptor Inhibitors

不可逆雌激素受体抑制剂

基本信息

批准号：
10684742
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/10684742
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 Detection Neoplasm Metastasis Oral Outcome Patients Permeability Pharmacodynamics Pharmacologic Actions Plasma Proteins Productivity Proliferating 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 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.

项目概要雌激素受体（ER）配体结合域（LBD）中出现了组成型活性体细胞突变作为转移性 ER+ 乳腺癌患者内分泌治疗耐药的常见机制。不幸的是，没有治疗药物可以治疗这一患者群体。长期目标是发展治疗上有用的不可逆 ER 抑制剂，用于治疗 ER+ 转移性乳腺癌，这将为当前治疗失败或复发的个体创建治疗选择。总体目标是鉴定基于模板的不可逆 ER 抑制剂，这些抑制剂可以高亲和力与 ER 结合并形成与 ER LBD 中的 C530 氨基酸残基形成不可逆共价 C-S 键。中心假设是药物优化的不可逆 ER 抑制剂可以通过结合临床证明的 ER- 结合基序和分子中形成共价键的迈克尔加成部分。这个假设是由早期基于三苯乙烯的不可逆 ER 拮抗剂支持，表现出类似于他莫昔芬，以及我们实验室的原型化合物，以噻吩（雷洛昔芬样）为核心，展示了缺乏这种作用，但在乳房中具有同样有效的拮抗作用。中心假设将通过追求三个具体目标：1）不可逆ER抑制剂的设计和合成； 2) 确定影响不可逆 ER 抑制剂对乳腺癌细胞增殖的影响，以及 3) 评估体内药效学和新型不可逆ER抑制剂的抗肿瘤治疗功效。第一个目标是不可逆的ER结合抑制剂将使用核心基序合成：三苯乙烯（他莫昔芬样）和苯并噻吩（雷洛昔芬样），预计具有高度选择性、有效并发挥永久拮抗作用。下目标第二，将评估合成的化合物与ER C530形成共价键的能力和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代理将确定用于进一步的临床前研究和患者来源的异种移植乳腺肿瘤模型的疗效。这这里的研究具有创新性，因为它的重点是使用不可逆抑制剂来克服内分泌抵抗并结合新的部分以实现高药物暴露。这一贡献意义重大，因为它将鉴定出一类不可逆的 ER 抑制剂，它们表现出新颖的抗雌激素作用，缺乏激动剂活性，并且具有较高的口服生物利用度，为乳腺治疗创新疗法的开发提供了新的机遇癌症。