Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Anticancer Agents Med Chem. 2013 May;13(4):532-45. doi: 10.2174/1871520611313040002.
Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays an important role in survival. We developed a novel approach, targeting FAK-protein interactions by computer modeling and screening of NCI small molecule drug database. In this report we targeted FAK and Mdm-2 protein interaction to decrease tumor growth. By macromolecular modeling we found a model of FAK and Mdm-2 interaction and performed screening of > 200,000 small molecule compounds from NCI database with drug-like characteristics, targeting the FAK-Mdm-2 interaction. We identified 5';-O-Tritylthymidine, called M13 compound that significantly decreased viability in different cancer cells. M13 was docked into the pocket of FAK and Mdm-2 interaction and was directly bound to the FAK-N terminal domain by ForteBio Octet assay. In addition, M13 compound affected FAK and Mdm-2 levels and decreased complex of FAK and Mdm-2 proteins in breast and colon cancer cells. M13 re-activated p53 activity inhibited by FAK with Mdm-2 promoter. M13 decreased viability, clonogenicity, increased detachment and apoptosis in a dose-dependent manner in BT474 breast and in HCT116 colon cancer cells in vitro. M13 decreased FAK, activated p53 and caspase-8 in both cell lines. In addition, M13 decreased breast and colon tumor growth in vivo. M13 activated p53 and decreased FAK in tumor samples consistent with decreased tumor growth. The data demonstrate a novel approach for targeting FAK and Mdm-2 protein interaction, provide a model of FAK and Mdm-2 interaction, identify M13 compound targeting this interaction and decreasing tumor growth that is critical for future targeted therapeutics.
黏着斑激酶（FAK）在多种肿瘤中过度表达，在存活中发挥重要作用。我们通过计算机建模和 NCI 小分子药物数据库筛选开发了一种新的方法，靶向 FAK-蛋白相互作用。在本报告中，我们针对 FAK 和 Mdm-2 蛋白相互作用以减少肿瘤生长。通过大分子建模，我们发现了 FAK 和 Mdm-2 相互作用的模型，并对具有药物样特征的 NCI 数据库中的>200,000 种小分子化合物进行了筛选，以靶向 FAK-Mdm-2 相互作用。我们鉴定出 5'-O-三苯甲基胸苷，称为 M13 化合物，可显著降低不同癌细胞的活力。M13 被对接进入 FAK 和 Mdm-2 相互作用的口袋中，并通过 ForteBio Octet 测定直接与 FAK-N 端结构域结合。此外，M13 化合物影响 FAK 和 Mdm-2 水平，并降低乳腺癌和结肠癌细胞中 FAK 和 Mdm-2 蛋白的复合物。M13 化合物通过 Mdm-2 启动子重新激活被 FAK 抑制的 p53 活性。M13 以剂量依赖性方式降低 BT474 乳腺癌和 HCT116 结肠癌细胞系中的活力、集落形成能力、增加细胞脱落和凋亡。M13 在两种细胞系中均降低了 FAK、激活了 p53 和 caspase-8。此外，M13 在体内降低了乳腺癌和结肠癌的肿瘤生长。M13 在肿瘤样本中激活了 p53 并降低了 FAK，与肿瘤生长减少一致。数据表明了一种新的靶向 FAK 和 Mdm-2 蛋白相互作用的方法，提供了 FAK 和 Mdm-2 相互作用的模型，鉴定了靶向该相互作用并降低肿瘤生长的 M13 化合物，这对于未来的靶向治疗至关重要。
