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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.

项目总结