Anti-Angiogenic and Tumorcidal Drugs Against 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，常规治疗提供的益处非常有限。因此，新的治疗方法，以改善这种疾病的结果是至关重要的。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使人们对靶向受体酪氨酸激酶的新疗法的开发重新产生了兴趣并提高了乐观态度。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表达、激活，有时甚至突变。SF/HGF与其受体的结合不仅促进肿瘤细胞的生长，而且促进肿瘤新血管系统内衬的内皮细胞的生长。c-Met-SF/HGF途径的拮抗作用代表了一种有吸引力的杀肿瘤和抗血管生成方法，这种双向机制可能会降低治疗诱导的耐药性的发生率。我们的初步研究已经确定了ANG-797，这是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显著和选择性地抑制c-Met活化，并抑制SF/HGF启动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，在腹腔内或口服给予ANG-797后，具有原位植入脑肿瘤的动物具有显著的生存益处。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是体内高水平抗肿瘤活性的原因，尽管对单个肿瘤生长相关RTK靶标的体外IC 50较高。我们认为，ANG-797的效力可以通过合理地修饰其2，4-二氨基喹唑啉骨架上的取代基来提高。最近，通过使用分子模拟和药物化学方法，我们已经产生了103个新的ANG-797类似物：37个2位类似物和66个4位修饰的类似物。这些修饰允许扩展这一系列化合物，并有可能显著降低对激酶靶点的IC 50。在较新的化合物中，ANG-1490和ANG-2201在我们基于细胞的筛选试验中对两种靶点的效力都有所增加。有趣的是，我们的初步体内研究表明，ANG-1490和ANG-2201对皮下NSCLC A549肿瘤有效。在本申请中，我们建议在多个筛选中确认ANG-1490和ANG-2201的选择性和效力的改善水平，并充分评估这些化合物对肺癌细胞系中的增殖和信号转导的抗肺癌作用。此外，从我们正在进行的化学项目中出现的具有相同或更好效价和选择性的任何新类似物将被纳入这些评价中。我们还将确定最小有效剂量，并更好地了解体外作用机制。拟定的体内研究将提供关于这些抗血管生成和肿瘤杀灭剂抑制肺肿瘤生长和延长小鼠模型存活期的能力的重要临床前有效性数据。这些初步研究将支持正在进行的新药开发，该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的治疗强调需要新的治疗方法。针对c-Met的小分子抑制剂作为抗肿瘤和抗血管生成药物在肺癌的治疗中具有重要的应用前景。

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.