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

• 批准号: 10359449
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359449
• 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; Time; Tissues; Tube; Tyrosine; Uterus; Woman; antagonist; base; bone; cancer cell; cancer diagnosis; clinically significant; cohort; combinatorial; 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

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 乳腺癌是最常被诊断出的癌症，也是美国的第二大死亡原因 女性。大多数乳腺癌（约75％）表达雌激素受体α（ERα）蛋白，因此 通过内分泌疗法抑制这种蛋白质功能是ER阳性乳腺癌治疗的支柱 患者。尽管如此，在接受内分泌治疗的几乎一半的女性中，获得的抵抗已经发展 与患者生存不良有关的治疗。具体而言，在大量案例中，延长了 用内分泌疗法治疗会产生抗性肿瘤细胞的发展，从而创造出肿瘤 复发，表现为非常困难的转移性疾病。最近，深DNA 测序已确定了大部分患者的ERα基因（ESR1）的特定部位的体细胞突变 乳腺癌的传播。具体而言，Y537和D538G突变使ERα具有抗电流 内分泌疗法，因此，开发一种新颖的靶向疗法来解决这些临床很重要 通过使用下一代ERα拮抗剂抑制ERα突变蛋白来挑战。我们的长期目标是 开发更有效，更安全的小分子药物，以阻止组成性活跃的突变体治疗 耐内分泌转移性乳腺癌，有可能显着改善当前疗法 定位策略。该R21应用的短期目标是识别和开发特定的类似药物样 通过使用DNA编码的化学物质，探针和提名临床前候选者靶向ER突变蛋白 库（DEL）筛选平台。该提案的目的将通过解决以下内容来评估 具体目的：1。我们将执行DNA编码的化学文库筛选到身份小分子粘合剂到 突变ERα蛋白的配体结合结构域。 2。我们将通过使用验证和优先考虑铅化合物 生化和功能研究。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乳腺癌中的ERα突变体功能。这项研究将为 基础工作，用于对未来应用的更详细的后续研究。成功执行此提议后 研究计划，我们希望已经确定了突变ER的铅化合物，可以将其用于未来 临床和临床研究。