Anti-Angiogenic and Tumorcidal Drugs Against Lung Carcinoma

抗肺癌的抗血管生成和抗肿瘤药物

• 批准号: 7394773
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 20.06万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394773
• 关键词: A549; ANG gene; Accounting; Angiogenesis Inhibitors; Animals; Binding; Binding Sites; Biological Assay; Brain Neoplasms; Cancer Etiology; Cancer cell line; Cell Proliferation; Cells; Cessation of life; Chemistry; Class; Clinical; Data; Death Rate; Development; Disease; Disease Outcome; Dose; Endothelial Cells; Evaluation; Event; Growth; Hepatocyte Growth Factor; Human; Implant; In Vitro; Incidence; Individual; Inhibitory Concentration 50; Intervention; Lead; Lung; Lung Neoplasms; Malignant neoplasm of lung; Modification; Mus; Mutate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oral; Oral Administration; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Positioning Attribute; Protein Overexpression; Receptor Protein-Tyrosine Kinases; Resistance; Role; Route; Screening procedure; Series; Severe Combined Immunodeficiency; Signal Transduction; Solid Neoplasm; Stress; Testing; Therapeutic; Therapeutic Agents; Tumor Cell Biology; Tumor Cell Line; Tumor Tissue; Tumor-Associated Vasculature; analog; angiogenesis; angiogenin; base; cancer cell; cell growth; chemical property; diaminoquinazoline; improved; in vivo; inhibitor/antagonist; interest; kinase inhibitor; lung Carcinoma; migration; molecular modeling; mouse model; neoplastic cell; novel; novel therapeutics; optimism; pre-clinical; programs; receptor; research clinical testing; scaffold; small molecule; subcutaneous; success; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Lung cancer is the world's leading cause of cancer deaths, with conventional therapies offering very limited benefit. Therefore, novel therapeutic approaches to improve outcomes of this disease are critical. Recent advances in tumor cell biology have led to renewed interest and heightened optimism in the development of new therapeutics targeting receptor tyrosine kinases, given their essential roles in tumor growth, invasion, metastasis and angiogenesis. In particular, c-Met, the receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF), has been identified as a therapeutic target against tumorigenesis. c-Met is over-expressed or mutated in a variety of solid tumors. There is strong evidence that c-Met is overexpressed, activated, and sometimes mutated in lung cancer cell lines and tumor tissues. Binding of SF/HGF to its receptor promotes growth not only of tumor cells, but also of the endothelial cells lining the tumor neovasculature. Antagonism of the c-Met-SF/HGF pathway represents an attractive tumoricidal and anti- angiogenic approach and such a bi-faceted mechanism potentially can lower the incidence of therapy-induced resistance. Our preliminary studies have identified ANG-797, an active, small molecule kinase inhibitor that competes with ATP for the ATP-binding site of c-Met. Encouraging results indicate that ANG-797 significantly and selectively inhibits c-Met activation and inhibits downstream signaling events initiated by SF/HGF. In vitro, ANG-797 inhibits endothelial and tumor cell growth and SF/HGF-induced angiogenesis. In vivo data reveal a significant survival benefit to animals bearing orthotopically implanted brain tumors after i.p. or oral administration of ANG-797. Recent studies have demonstrated that ANG-797 also inhibits activity of a second RTK associated with angiogenesis, Tie-2, and the dual inhibitory activities of the compound towards these RTKs may account for the high level of anti-tumor activity in vivo despite high nanomolar in vitro IC50s towards the individual tumor growth-related RTK targets. We believe that the potency of ANG-797 can be improved by rationally modifying substituents on its 2,4-diaminoquinazoline scaffold. Recently, by using molecular modeling and medicinal chemistry approaches, we have generated 103 new ANG-797 analogs: thirty-seven 2- positional analogs and Sixty-six modified at the 4-position. These modifications allow expansion of this series of compounds and the potential to significantly decrease the IC50 against the kinase targets. Among the newer compounds, ANG-1490 and ANG-2201 have increased potency against both targets in our cell-based screening assays. Interestingly, our pilot in vivo studies suggest that ANG-1490 and ANG-2201 are efficacious against subcutaneous NSCLC A549 tumors. In the current application, we propose to confirm the improved levels of selectivity and potency of ANG-1490 and ANG-2201 in multiple screens, and fully evaluate the anti-lung cancer effects of these compounds on the proliferation and signal transduction in lung cancer cell lines. In addition, any newer analogs emerging from our ongoing chemistry program with the same or better potency and selectivity will be included in these evaluations. We will also determine the minimal effective dose and better understand the mechanism of action in vitro. The proposed in vivo studies will provide important preclinical efficacy data regarding the ability of these anti-angiogenic and tumorcidal agents to inhibit lung tumor growth and prolong survival in mouse models. These initial studies will support the ongoing development of a new drug with potential clinical benefits to a disease urgently needing better interventions. The high death rate of lung cancer and the lack of an effective therapy stress the need for novel therapeutics. Small molecule inhibitors against c-Met as anti-tumor and anti-angiogenic agents have important therapeutic potential for the treatment of human lung carcinoma.

描述（由申请人提供）：肺癌是世界上癌症死亡的主要原因，传统疗法提供的益处非常有限。因此，改善这种疾病结果的新治疗方法至关重要。鉴于受体酪氨酸激酶在肿瘤生长、侵袭、转移和血管生成中的重要作用，肿瘤细胞生物学的最新进展引起了人们对开发针对受体酪氨酸激酶的新疗法的新兴趣和高度乐观。特别是，c-Met（肝细胞生长因子/分散因子（HGF/SF）的受体酪氨酸激酶）已被确定为抗肿瘤发生的治疗靶点。 c-Met 在多种实体瘤中过度表达或突变。有强有力的证据表明，c-Met 在肺癌细胞系和肿瘤组织中过度表达、激活，有时甚至发生突变。 SF/HGF与其受体的结合不仅促进肿瘤细胞的生长，而且促进肿瘤新生血管内皮细胞的生长。 c-Met-SF/HGF 途径的拮抗代表了一种有吸引力的杀肿瘤和抗血管生成方法，并且这种双向机制可能会降低治疗引起的耐药性的发生率。我们的初步研究已确定 ANG-797，一种活性小分子激酶抑制剂，可与 ATP 竞争 c-Met 的 ATP 结合位点。令人鼓舞的结果表明，ANG-797 显着且选择性地抑制 c-Met 激活并抑制 SF/HGF 引发的下游信号传导事件。在体外，ANG-797 抑制内皮细胞和肿瘤细胞生长以及 SF/HGF 诱导的血管生成。体内数据显示，腹腔注射后原位植入脑肿瘤的动物具有显着的生存益处。或口服ANG-797。最近的研究表明，ANG-797 还抑制与血管生成相关的第二种 RTK Tie-2 的活性，并且该化合物对这些 RTK 的双重抑制活性可能解释了尽管高纳摩尔浓度，但其在体内具有高水平的抗肿瘤活性。针对个体肿瘤生长相关 RTK 靶标的体外 IC50。我们相信，通过合理修饰其2,4-二氨基喹唑啉支架上的取代基可以提高ANG-797的效力。最近，通过使用分子建模和药物化学方法，我们生成了 103 个新的 ANG-797 类似物：37 个 2 位类似物和 66 个 4 位修饰类似物。这些修饰允许扩展该系列化合物，并有可能显着降低针对激酶靶标的 IC50。在新化合物中，ANG-1490 和 ANG-2201 在我们基于细胞的筛选试验中增强了针对这两个靶标的效力。有趣的是，我们的体内试验研究表明 ANG-1490 和 ANG-2201 对皮下 NSCLC A549 肿瘤有效。在目前的申请中，我们计划在多次筛选中确认ANG-1490和ANG-2201的选择性和效力水平的提高，并全面评估这些化合物对肺癌细胞增殖和信号转导的抗肺癌作用线。此外，我们正在进行的化学计划中出现的任何具有相同或更好效力和选择性的新类似物都将包含在这些评估中。我们还将确定最小有效剂量并更好地了解体外作用机制。拟议的体内研究将提供有关这些抗血管生成和杀肿瘤药物抑制肺肿瘤生长和延长小鼠模型生存能力的重要临床前疗效数据。这些初步研究将支持一种新药的持续开发，这种新药对迫切需要更好干预的疾病具有潜在的临床益处。肺癌的高死亡率和缺乏有效治疗方法强调了对新疗法的需求。 c-Met 小分子抑制剂作为抗肿瘤和抗血管生成剂，对于治疗人类肺癌具有重要的治疗潜力。