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: 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
• 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

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 女性。大多数乳腺癌 (~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 患者。然而，近一半接受内分泌治疗的女性已经产生了获得性耐药性。 与患者生存率低相关的治疗。具体来说，在相当多的情况下，长期 内分泌治疗会产生耐药性肿瘤细胞，从而导致肿瘤 复发，表现为极难控制的转移性疾病。最近，深层DNA 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 患有已经扩散的乳腺癌。具体来说，Y537S 和 D538G 突变使 ERα 对当前的 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 通过使用下一代 ERα 拮抗剂抑制 ERα 突变蛋白来应对挑战。我们的长期目标是 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 目标定位策略。 R21申请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 文库（DEL）筛选平台。将通过解决以下问题来评估该提案的目标 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. 我们将使用以下方法验证先导化合物并确定其优先顺序 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 对ERα突变体的特异性可以抑制ERα突变体在乳腺癌中的功能。这项研究将奠定 为未来应用的更详细的后续研究奠定基础。成功执行此提议后 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。