Development of BRCA1-mimetic drugs for breast cancer

乳腺癌 BRCA1 模拟药物的开发

• 批准号: 8403554
• 负责人: Eliot M. Rosen
• 金额: $ 52.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-09 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403554
• 关键词: Affinity; Binding; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Cancer cell line; Cancer-Predisposing Gene; Cell Proliferation; Clinical; Complex; Development; Dose; Drug usage; Estradiol; Estrogen Antagonists; Estrogen Receptor 1; Estrogen Receptors; Estrogens; Exhibits; Female Breast Carcinoma; Gene Expression; Genes; Genetic Models; Genomics; Goals; Growth; Hereditary Malignant Neoplasm; Hormones; Hot Spot; Human; Incidence; Inherited; Lead; Length; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mammary gland; Maps; Mediating; Modeling; Mus; Mutation; Nude Mice; Pathogenesis; Pharmaceutical Preparations; Physiological; Prevention; Protein Isoforms; Proteins; Raloxifene; Reporter; Reporting; Repression; Research; Resistance; Resolution; Response Elements; Role; Selective Estrogen Receptor Modulators; Staging; Surface Plasmon Resonance; Tamoxifen; Testing; Toxic effect; Transgenic Model; Tumor Suppression; Tumor Suppressor Proteins; Variant; Wild Type Mouse; Xenograft Model; Xenograft procedure; analog; base; cancer type; carcinogenesis; early onset; estrophilin; high risk; in vivo; malignant breast neoplasm; mimetics; mutation carrier; novel; prevent; protein structure; public health relevance; screening; small molecule; small molecule libraries; three-dimensional modeling; tumor; tumor growth; tumorigenesis; virtual

DESCRIPTION (provided by applicant): We have studied the functional interaction of the breast cancer susceptibility gene-1 (BRCA1) and the estrogen receptor (ER-1) for the past 10 years. During these studies, we observed that BRCA1 strongly inhibits ER-1 activity in breast cancer cells and blocks estrogen (E2)-stimulated gene expression and cell proliferation. The BRCA1 repression of ER-1 activity is due to a physical interaction of the BRCA1 and ER- 1 proteins, which we mapped at high resolution. From these studies, we generated a 3D model of the BRCA1: ER-1 complex and performed virtual screening of a small molecule library to identify compounds that might act as "BRCA1-mimetics" to insert deeply into ER-1 at key contact points. Of 40 such compounds that we tested, 6 strongly inhibited ER-1 activity, including several that yielded 50% inhibition at concentrations of only 3-4 <M. Hypothesis. BRCA1 mediates a number of functions, including its role as a caretaker gene in preserving genomic integrity. However, this role for BRCA1 does not explain why mutation carriers exhibit an excess incidence of specific tumor types, particularly breast cancer. We hypothesize that while its caretaker function contributes to tumor suppression, BRCA1 suppression of breast cancer development requires its ability to inhibit ER-1 activity. Conversely, it will be possible to prevent breast cancer by restoring or enhancing this function, using small molecule compounds that mimic critical aspects of the BRCA1: ER-1 physical interaction. Objectives. To test this hypothesis, we will carry out four specific aims: 1) To study the mechanism of action of "BRCA1-mimetic" drugs in human breast cancer cells; 2) To generate large quantities of our current lead compounds and synthesize structural analogs of the lead compounds to produce more potent compounds; 3) To test the lead compound and best analog(s) for their ability to inhibit estrogen-stimulated human breast cancer tumor growth in vivo in a xenograft model; and 4) To test the ability of several compounds to prevent the early stages of mammary cancer development in several mouse transgenic models. Significance. Our ultimate goal is to develop novel drugs for breast cancer prevention and/or treatment. Importantly, the BRCA1-mimetic compounds interact with ER-1 in a manner that is distinct from that of the selective estrogen receptor modulators (SERMs), such as Tamoxifen and Raloxifene. Thus, they may be useful by themselves, in combination with existing agents, or in cases of hormone-resistant breast cancer.

描述（由申请人提供）：在过去的10年中，我们研究了乳腺癌易感基因-1（BRCA 1）和雌激素受体（ER-1）的功能相互作用。在这些研究中，我们观察到BRCA 1强烈抑制乳腺癌细胞中的ER-1活性，并阻断雌激素（E2）刺激的基因表达和细胞增殖。BRCA 1对ER-1活性的抑制是由于BRCA 1和ER- 1蛋白的物理相互作用，我们以高分辨率绘制了这一图谱。从这些研究中，我们生成了BRCA 1：ER-1复合物的3D模型，并对小分子文库进行了虚拟筛选，以鉴定可能作为“BRCA 1模拟物”在关键接触点深入插入ER-1的化合物。在我们测试的40种这样的化合物中，6种强烈抑制ER-1活性，包括几种在仅3-4 μ M的浓度下产生50%抑制的化合物。假说. BRCA 1介导许多功能，包括其作为保护基因组完整性的看护基因的作用。然而，BRCA 1的这种作用并不能解释为什么突变携带者表现出特定肿瘤类型的过度发病率，特别是乳腺癌。我们假设，虽然其看护功能有助于肿瘤抑制，但BRCA 1抑制乳腺癌发展需要其抑制ER-1活性的能力。相反，通过恢复或增强这种功能，使用模拟BRCA 1：ER-1物理相互作用的关键方面的小分子化合物，将有可能预防乳腺癌。目标.为了验证这一假设，我们将进行四个具体目标：1）研究“BRCA 1模拟物”药物在人类乳腺癌细胞中的作用机制; 2）大量产生我们目前的先导化合物，并合成先导化合物的结构类似物，以产生更有效的化合物; 3）测试先导化合物和最佳类似物在异种移植模型中体内抑制雌激素刺激的人乳腺癌肿瘤生长的能力;和4）测试几种化合物在几种小鼠转基因模型中预防乳腺癌发展的早期阶段的能力。意义我们的最终目标是开发用于预防和/或治疗乳腺癌的新药。重要的是，BRCA 1-模拟化合物与ER-1的相互作用方式不同于选择性雌激素受体调节剂（SERM），如他莫昔芬和雷洛昔芬。因此，它们可以单独使用，与现有药物联合使用，或在耐药乳腺癌的情况下使用。