Old Drugs and New Strategies for Tumor Metastasis

老药与肿瘤转移新策略

• 批准号: 8066654
• 负责人: ANNE R BRESNICK
• 金额: $ 24.15万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066654
• 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; Health; Human; 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; 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性肿瘤，迁移到体内远处并建立继发性肿瘤的能力。从临床角度来看，预防或抑制转移对于癌症治疗至关重要。 S100A4是钙结合蛋白的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不仅是转移性疾病的标志物，而且在转移性进展中具有直接作用。这些观察结果表明S100A4是治疗干预的绝佳目标。我们使用了一种新型的基于生物传感器的测定方法来识别S100A4的一系列小分子抑制剂，并定义了负责通过高分辨率X射线晶体学结合的原子决定因素。这些研究支持具有增强性和选择性增强的第二代S100A4抑制剂的发展。我们将使用荧光极化测定法对基于生物传感器的测定进行补充，以鉴定直接破坏S100A4/肌球蛋白-IIA相互作用的小分子抑制剂。两种测定法的铅化合物将被表征和优化。结构研究将确定S100A4抑制中涉及的化学和结构决定因素。生化分析将检查铅化合物的选择性和效力，以及小分子抑制剂阻止S100A4激活并干扰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原理证明S100A4抑制剂会影响癌细胞的运动和侵入性能力。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对可以作为治疗转移性癌症的治疗铅的化合物的鉴定和表征。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治疗至关重要。大量研究表明，S100A4是S100钙结合蛋白家族的成员，在转移性进展中具有直接作用。这些观察结果表明S100A4是治疗干预的绝佳目标。我们提出的研究涉及有效和选择性S100A4抑制剂的开发和测试。这些研究的完成将是化合物的鉴定和表征，这些化合物可以用作治疗转移性癌症的治疗铅。

项目成果

S100A4 regulates macrophage chemotaxis.

• DOI: 10.1091/mbc.e09-07-0609
• 发表时间: 2010-08-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Li ZH;Dulyaninova NG;House RP;Almo SC;Bresnick AR
• 通讯作者: Bresnick AR

Advantages of Molecular Weight Identification during Native MS Screening.

• DOI: 10.1055/a-0608-4870
• 发表时间: 2018-11
• 期刊: Planta medica
• 影响因子: 2.7
• 作者: Khan A;Bresnick A;Cahill S;Girvin M;Almo S;Quinn R
• 通讯作者: Quinn R

Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells.

• DOI: 10.1038/onc.2012.383
• 发表时间: 2013-08-08
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Chen, M.;Bresnick, A. R.;O'Connor, K. L.
• 通讯作者: O'Connor, K. L.

A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy.

• DOI: 10.1126/scitranslmed.3007410
• 发表时间: 2014-01-08
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Bruhn S;Fang Y;Barrenäs F;Gustafsson M;Zhang H;Konstantinell A;Krönke A;Sönnichsen B;Bresnick A;Dulyaninova N;Wang H;Zhao Y;Klingelhöfer J;Ambartsumian N;Beck MK;Nestor C;Bona E;Xiang Z;Benson M
• 通讯作者: Benson M