Development of a Precision Drug to target Y537S Mutant Estrogen Receptor in Metastatic Breast Cancer

开发针对转移性乳腺癌 Y537S 突变雌激素受体的精准药物

基本信息

批准号：
10540347
负责人：
Murugesan Palaniappan
金额：
$ 8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2021-12-13 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540347
关键词：
Address Affinity American Aromatase Inhibitors Bar Codes Binding Biochemical Biological Assay Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cause of Death Cells Characteristics Chemicals Clinic Clinical Clinical Research Clinical Treatment Collection DNA DNA sequencing Development Disease Drug Targeting Drug usage ESR1 gene Endocrine Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Estrogens Exposure to Follow-Up Studies Foundations Frequencies Fulvestrant Future Genes Genomics Goals Hormones Lead Libraries Ligand Binding Domain Malignant Neoplasms Metastatic breast cancer Modeling Mutation NCOA3 gene Neoplasm Metastasis Organoids Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Precision therapeutics Premenopause Production Protein Binding Domain Protein Inhibition Proteins Refractory Relapse Research Research Project Grants Resistance Resistance development Scanning Selective Estrogen Receptor Modulators Series Serine Signal Transduction Site Somatic Mutation Specificity Tamoxifen Testing Tissues Tube Tyrosine Uterus Woman antagonist bone cancer cell cancer diagnosis clinically significant cohort combinatorial drug-like compound genome editing hormone therapy improved inhibitor interest malignant breast neoplasm mutant neoplastic cell new therapeutic target next generation next generation sequencing novel patient subsets personalized medicine pre-clinical precision drugs precision oncology preclinical evaluation preclinical study protein function recruit screening side effect small molecule small molecule inhibitor small molecule libraries targeted treatment therapeutic target therapy resistant tumor

项目摘要

ABSTRACT Breast cancer is the most frequently diagnosed cancer and the second leading cause of death in American women. The majority of breast cancer (~75%) expresses estrogen receptor α (ERα) protein and therefore inhibition of this protein function by endocrine therapy is the mainstay of treatment in ER-positive breast cancer patients. Nevertheless, acquired resistance has developed in nearly half of women treated with endocrine therapy that is associated with poor patient survival. Specifically, in a substantial number of cases, prolonged treatment with endocrine therapy creates the development of resistant tumor cells and, consequently, tumor relapse, which manifests as metastatic disease that is extremely difficult to manage. Recently, deep DNA sequencing has identified somatic mutations at specific sites in the ERα gene (ESR1) in a large subset of patients with breast cancers that have spread. Specifically, Y537S and D538G mutations make ERα resistant to current endocrine therapy and therefore, it is important to develop a novel targeted therapy to address these clinical challenges by inhibiting ERα mutant proteins using next-generation ERα antagonist. Our long-term goal is to develop more effective and safer small molecule drugs that block constitutively active mutant ER for treating endocrine resistant metastatic breast cancer and have the potential to significantly improve current therapeutic targeting strategies. The short-term goal of this R21 application is to identify and develop specific drug-like probes and nominate preclinical candidates to target ER mutant protein by using a DNA-encoded chemical library (DEL) screening platform. The objective of this proposal will be evaluated by addressing the following specific aims: 1. We will perform DNA-encoded chemical libraries screen to identity small-molecule binders to the ligand-binding domain of mutant ERα protein. 2. We will validate and prioritize lead compounds by using biochemical and functional studies. Our central hypothesis is that small molecule antiestrogens with high affinity and specificity for ERα mutants can inhibit ERα mutant function in breast cancer. This research will lay the groundwork for more detailed follow up studies for future applications. After successful execution of this proposed research plan, we expect to have identified lead compounds for mutant ER and that can be used for future pre- clinical and clinical studies.

抽象的乳腺癌是美国人最常诊断出的癌症，也是第二大死亡原因大多数乳腺癌（约 75%）表达雌激素受体 α (ERα) 蛋白，因此。通过内分泌治疗抑制这种蛋白质功能是 ER 阳性乳腺癌的主要治疗方法然而，近一半接受内分泌治疗的女性出现了获得性耐药。具体来说，在很多情况下，这种治疗会导致患者生存期延长。内分泌治疗会产生耐药性肿瘤细胞，从而导致肿瘤复发，表现为最近极难控制的转移性疾病。测序已在大部分患者中发现了 ERα 基因 (ESR1) 特定位点的体细胞突变具体来说，Y537S 和 D538G 突变使 ERα 对当前的乳腺癌具有抵抗力。内分泌治疗，因此，开发一种新的靶向治疗来解决这些临床问题非常重要我们的长期目标是通过使用下一代 ERα 拮抗剂抑制 ERα 突变蛋白来应对挑战。开发更有效、更安全的小分子药物，阻断组成型活性突变 ER 的治疗内分泌抵抗性转移性乳腺癌，有可能显着改善目前的治疗该 R21 应用的短期目标是识别和开发特定的类药物。使用 DNA 编码的化学物质探测并提名临床前候选药物来靶向 ER 突变蛋白图书馆（DEL）筛选平台将通过解决以下问题进行评估。具体目标： 1. 我们将进行 DNA 编码的化学库筛选，以识别小分子结合物突变 ERα 蛋白的配体结合域 2. 我们将使用先导化合物进行验证和优先排序。我们的中心假设是具有高亲和力的小分子抗雌激素。 ERα突变体的特异性可以抑制ERα突变体在乳腺癌中的功能。为未来应用的更详细后续研究奠定基础。研究计划中，我们希望能够鉴定出突变 ER 的先导化合物，并可用于未来的预研究。临床和临床研究。