Old Drugs and New Strategies for Tumor Metastasis

老药与肿瘤转移新策略

• 批准号: 7466346
• 负责人: ANNE R BRESNICK
• 金额: $ 24.9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-04 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466346
• 关键词: Address; Affect; Affinity; Animal Model; Animals; Benign; Binding; Binding Proteins; Biochemical; Biological Assay; Biosensor; Calcium-Binding Proteins; Cause of Death; Cells; Chemicals; Clinical; Complement; Crystallography; Development; Disease; Disseminated Malignant Neoplasm; Distant; Evaluation; Family; Fluorescence Polarization; Generations; Human; Invasive; Lead; Left; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Myosin Type II; Neoplasm Metastasis; Nonmuscle Myosin Type IIA; Outcome Study; Patients; Pharmaceutical Preparations; Prevention; Primary Neoplasm; Process; Proteins; Public Health; Regulation; Resolution; Role; Series; Site; Structure; Testing; Therapeutic; Therapeutic Intervention; base; cancer cell; cancer therapy; cell motility; design; high throughput screening; inhibitor/antagonist; malignant breast neoplasm; member; novel; prevent; small molecule; tumor

DESCRIPTION (provided by applicant): The leading cause of death associated with cancer is tumor metastasis. Metastasis is the ability of malignant cells to leave the primary tumor, migrate to distant sites in the body and establish secondary tumors. From a clinical standpoint, the prevention or inhibition of metastasis is vital to the treatment of cancer. S100A4, a member of the S100 family of calcium-binding proteins, regulates carcinoma cell motility via interactions with myosin-II. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. We used a novel biosensor-based assay to identify a series of small molecule inhibitors of S100A4 and defined the atomic determinants responsible for binding by high resolution x-ray crystallography. These studies are supporting the development of second generation S100A4 inhibitors with enhanced affinity and selectivity. We will complement our biosensor-based assay with a fluorescence polarization assay to identify small molecule inhibitors that directly disrupt the S100A4/myosin-IIA interaction. Lead compounds from both assays will be characterized and optimized. Structural studies will identify the chemical and structural determinants involved in S100A4 inhibition. Biochemical analyses will examine the selectivity and potency of lead compounds as well as the mechanisms by which small molecule inhibitors prevent S100A4 activation and interfere with S100A4-mediated regulation of myosin-IIA assembly. Cell-based studies will provide proof-of-principle that S100A4 inhibitors affect the motile and invasive capabilities of carcinoma cells. Using animal models of breast cancer, we will examine the efficacy of S100A4 inhibitors to limit and/or inhibit metastasis. The outcome of these studies will be the identification and characterization of compounds that may serve as therapeutic leads for the treatment of metastatic cancer. PUBLIC HEALTH RELEVANCE: The leading cause of death associated with cancer is tumor metastasis. From a clinical standpoint, the prevention or inhibition of metastasis is vital to the treatment of cancer. Numerous studies indicate that S100A4, a member of the S100 family of calcium-binding proteins, has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Our proposed studies address the development and testing of potent and selective S100A4 inhibitors. The completion of these studies will be the identification and characterization of compounds that may serve as therapeutic leads for the treatment of metastatic cancer.

描述（由申请人提供）：与癌症相关的死亡的主要原因是肿瘤转移。转移是恶性细胞离开原发肿瘤、迁移到体内较远部位并形成继发肿瘤的能力。从临床角度来看，预防或抑制转移对于癌症的治疗至关重要。 S100A4 是钙结合蛋白 S100 家族的成员，通过与肌球蛋白-II 相互作用来调节癌细胞运动。大量研究表明，S100A4 不仅仅是转移性疾病的标志物，而且在转移进展中具有直接作用。这些观察结果表明 S100A4 是治疗干预的绝佳靶点。我们使用一种新型的基于生物传感器的测定法来鉴定一系列 S100A4 小分子抑制剂，并通过高分辨率 X 射线晶体学确定了负责结合的原子决定因素。这些研究支持开发具有增强亲和力和选择性的第二代 S100A4 抑制剂。我们将用荧光偏振测定来补充基于生物传感器的测定，以识别直接破坏 S100A4/肌球蛋白-IIA 相互作用的小分子抑制剂。两种测定中的先导化合物都将被表征和优化。结构研究将确定参与 S100A4 抑制的化学和结构决定因素。生化分析将检查先导化合物的选择性和效力，以及小分子抑制剂阻止 S100A4 激活和干扰 S100A4 介导的肌球蛋白-IIA 组装调节的机制。基于细胞的研究将提供 S100A4 抑制剂影响癌细胞运动和侵袭能力的原理证明。使用乳腺癌动物模型，我们将检查 S100A4 抑制剂限制和/或抑制转移的功效。这些研究的结果将是鉴定和表征可作为治疗转移性癌症的先导化合物。公共卫生相关性：与癌症相关的死亡的主要原因是肿瘤转移。从临床角度来看，预防或抑制转移对于癌症的治疗至关重要。大量研究表明，S100A4 是钙结合蛋白 S100 家族的成员，在转移进展中具有直接作用。这些观察结果表明 S100A4 是治疗干预的绝佳靶点。我们提出的研究致力于开发和测试有效的选择性 S100A4 抑制剂。这些研究的完成将鉴定和表征可作为治疗转移性癌症的治疗先导化合物。