Novel c-Met and Tie-2 antagonists against human glioma

描述(申请人提供)：恶性胶质瘤是最常见的原发脑癌。尽管在诊断和治疗方面取得了进展，但这些肿瘤的复发率高，预后差，缺乏有效的治疗方法。肿瘤分子生物学的最新进展重新引起了人们对治疗人脑胶质瘤的新疗法的兴趣和高度乐观。受体酪氨酸激酶因其在肿瘤生长、侵袭、转移和血管生成中的重要作用而成为肿瘤治疗的主要靶点。C-Met是散布因子/肝细胞生长因子受体酪氨酸激酶(SF/HGF)，已被证明在包括胶质瘤在内的多种实体瘤中过表达或突变。SF/HGF与其受体的结合促进肿瘤细胞和肿瘤血供内皮细胞的生长。因此，拮抗c-Met-SF/HGF通路是一种有吸引力的多方面靶向肿瘤细胞的方法，也可能通过阻断参与疾病进展的多个事件来降低治疗诱导耐药的风险。在以前的工作中，我们发现了一类新的c-Met拮抗剂(先导化合物Ang 797)，它们竞争c-Met的ATP结合位点，阻断c-Met的激活，并抑制SF/HGF启动的下游信号事件。我们发现，Ang 797还针对另一种受体酪氨酸激酶，Tie-2，参与血管生成，特别是维持肿瘤新生血管。在体内，Ang 797可抑制人脑胶质瘤原位模型中的肿瘤生长并提高存活率。最近的数据表明，ANG 797的活性和选择性可以通过对其2，4-二氨基喹唑啉支架上的取代基进行修饰来提高。特别是，Ang 1490是一种新制备的Ang 797类似物，在4位具有不同的取代基，显示出12倍的抑制活性和对HGF/SF/c-Met途径的特异性，具有比Ang 797更好的水溶性。在初步的体内肺部肿瘤研究中，它显示出抗肿瘤活性，与Ang 797相比，活性有改善的趋势，但在统计学上没有显著意义。这一阶段的应用集中在2，4-二氨基喹唑啉支架的进一步优化上，目标是寻找更有效的c-Met/Tie-2拮抗剂，这些拮抗剂可以推进到临床开发。在最近活性显著提高的基础上，结合对新类似物对体外细胞和激酶靶标以及体内肿瘤模型的抑制活性的评估，额外的合成工作将集中于确定一种优化的先导化合物，以便在未来的SBIR第二阶段应用进入临床前开发。

DESCRIPTION (provided by applicant): Malignant glioma is the most commonly diagnosed primary brain cancer. Despite advances in diagnosis and therapy, these tumors show a high incidence of recurrence, have a poor prognosis and lack effective therapies. Recent advances in tumor molecular biology have led to renewed interest and heightened optimism for the development of new therapeutics for the treatment of human glioma. Receptor tyrosine kinases have become major targets for cancer therapy due to their critical roles in tumor growth, invasion, metastasis and angiogenesis. c-Met, the receptor tyrosine kinase for scatter factor/hepatocyte growth factor (SF/HGF) has been shown to be over-expressed or mutated in a variety of solid tumors including gliomas. Binding of SF/HGF to its receptor promotes growth of both tumor cells and endothelial cells lining the tumor's blood supply. Antagonism of the c-Met-SF/HGF pathway is thus an attractive multi-faceted approach to targeting the tumor cell that also may reduce the risk of therapy-induced resistance by blocking multiple events involved in disease progression. In previous work we identified a new class of c-Met antagonists (with lead compound ANG 797) that compete at the ATP-binding site of c-Met, block c-Met activation and inhibit down-stream signaling events initiated by SF/HGF. We found that ANG 797 also targets another receptor tyrosine kinase, Tie-2, involved in angiogenesis and in particular with sustaining tumor neovascularization. In vivo ANG 797 attenuates tumor growth and improves survival in orthotopic models of human glioma. Recent data have demonstrated that the activity and selectivity of ANG 797 can be improved by modifying substituents on its 2,4-diaminoquinazoline scaffold. In particular, ANG 1490, a newly prepared ANG 797 analog with a different substituent at the 4 position, shows 12-fold greater inhibitory activity and increased specificity to the HGF/SF/c-Met pathway, with better water solubility than ANG 797. In a preliminary in vivo lung tumor study it showed anti-tumor activity with a trend toward improved, but not statistically significant, activity over ANG 797. This Phase I application is focused on further optimization of the 2,4-diaminoquinazoline scaffold with the goal of identifying more potent c-Met/Tie-2 antagonists that can be advanced towards clinical development. Additional synthetic work based on the recent significant improvement in activity, in combination with assessment of inhibitory activity of new analogs towards in vitro cellular and kinase targets and in an in vivo tumor model, will be focused on identifying an optimized lead for entry into preclinical development in a future SBIR Phase 2 application.