Old Drugs and New Strategies for Tumor Metastasis

描述（由申请人提供）：与癌症相关的主要死亡原因是肿瘤转移。转移是恶性细胞离开原发性肿瘤，迁移到体内远端部位并建立继发性肿瘤的能力。从临床观点来看，预防或抑制转移对于癌症的治疗至关重要。S100 A4是钙结合蛋白S100家族的成员，通过与肌球蛋白II相互作用调节癌细胞运动。许多研究表明，S100 A4不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，S100 A4是治疗干预的极好靶点。我们使用了一种新的基于生物传感器的测定方法来鉴定一系列S100 A4的小分子抑制剂，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簇。这些研究支持开发具有增强的亲和力和选择性的第二代S100 A4抑制剂。我们将补充我们的基于生物传感器的检测与荧光偏振检测，以确定小分子抑制剂，直接破坏S100 A4/肌球蛋白-IIA相互作用。将对来自两种试验的先导化合物进行表征和优化。结构研究将确定参与S100 A4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S100 A4活化和干扰S100 A4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S100 A4抑制剂影响癌细胞的运动和侵袭能力的原理证明。使用乳腺癌的动物模型，我们将检查S100 A4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能作为治疗转移性癌症的治疗先导的化合物。公共卫生相关性：与癌症相关的主要死亡原因是肿瘤转移。从临床观点来看，预防或抑制转移对于癌症的治疗至关重要。大量研究表明，S100 A4，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，S100 A4是治疗干预的极好靶点。我们提出的研究解决了有效和选择性S100 A4抑制剂的开发和测试。这些研究的完成将是鉴定和表征可能作为治疗转移性癌症的治疗先导的化合物。

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.