Development of BRCA1-mimetic drugs for breast cancer

乳腺癌 BRCA1 模拟药物的开发

• 批准号: 8022946
• 负责人: Eliot M. Rosen
• 金额: $ 58.71万
• 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/8022946
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: BRCA1 (breast cancer 1, early onset) is a human gene that belongs to a class of genes known as tumor suppressors, which maintain genomic integrity to prevent uncontrolled proliferation. Inherited variations (mutations) in the BRCA1 gene have been implicated in several hereditary cancer types, including breast and ovarian cancers. The goal of this research is to develop small molecule drug-like compounds that mimic the ability of the BRCA1 protein to insert into the estrogen receptor protein and inhibit estrogen action. These "BRCA1-mimetic" compounds may be useful in the prevention and/or treatment of breast cancer.

描述（由申请人提供）：过去10年来，我们研究了乳腺癌易感性基因1（BRCA1）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BRCA1在乳腺癌细胞中强烈抑制ER-1活性，并阻止雌激素（E2）刺激的基因表达和细胞增殖。 ER-1活性的BRCA1抑制是由于BRCA1和ER-1蛋白的物理相互作用引起的，我们以高分辨率映射。从这些研究中，我们生成了BRCA1：ER-1复合物的3D模型，并对小分子库进行了虚拟筛选，以识别可能充当“ BRCA1-Mimetics”的化合物，以在关键接触点上深入插入ER-1。在我们测试的40种此类化合物中，有6种强烈抑制ER-1活性，其中几种仅在仅3-4 <m的浓度下产生50％的抑制作用。假设。 BRCA1介导了许多功能，包括其作为看守基因在保持基因组完整性中的作用。但是，BRCA1的这一作用并不能解释为什么突变载体表现出特定肿瘤类型的过度发生率，尤其是乳腺癌。我们假设其看守功能有助于抑制肿瘤，但BRCA1抑制乳腺癌的发展需要其抑制ER-1活性的能力。相反，使用模仿BRCA1：ER-1物理相互作用的临界方面的小分子化合物，可以通过恢复或增强该功能来预防乳腺癌。目标。为了检验这一假设，我们将执行四个特定的目的：1）研究人类乳腺癌细胞中“ BRCA1模拟”药物的作用机理； 2）生成大量的当前铅化合物并合成铅化合物的结构类似物，以产生更有效的化合物； 3）测试铅化合物和最佳类似物（S）在异种移植模型中抑制体内雌激素刺激的人类乳腺癌肿瘤生长的能力； 4）测试几种小鼠转基因模型中几种化合物防止乳腺癌发展早期阶段的能力。意义。我们的最终目标是开发用于预防乳腺癌和/或治疗的新型药物。重要的是，BRCA1模拟化合物以与选择性雌激素受体调节剂（Serm）（例如他莫昔芬和raloxifene）不同的方式与ER-1相互作用。因此，它们本身可能与现有药物或耐激素乳腺癌相结合。公共卫生相关性：BRCA1（乳腺癌1，早期发作）是一种属于一种称为肿瘤抑制子的基因的人类基因，它们保持基因组完整性以防止不受控制的增殖。 BRCA1基因中的遗传变异（突变）与几种遗传性癌症类型有关，包括乳腺癌和卵巢癌。这项研究的目的是开发小分子药物样化合物，以模仿BRCA1蛋白插入雌激素受体蛋白并抑制雌激素作用的能力。这些“ BRCA1模拟”化合物可能有助于预防和/或治疗乳腺癌。