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性脑癌。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。肿瘤分子生物学的最新进展使人们对胶质瘤治疗新疗法的发展重新产生了兴趣，并提高了人们的乐观情绪。受体酪氨酸激酶在肿瘤的生长、侵袭、转移和血管生成中起着重要作用，已成为癌症治疗的主要靶点。分散因子/肝细胞生长因子（SF/HGF）的受体酪氨酸激酶c-Met已被证明在包括胶质瘤在内的多种实体肿瘤中过度表达或突变。SF/HGF与其受体的结合促进肿瘤细胞和肿瘤血液供应的内皮细胞的生长。因此，c-Met-SF/HGF通路的拮抗是一种有吸引力的针对肿瘤细胞的多方面方法，也可能通过阻断与疾病进展有关的多种事件来降低治疗诱导的耐药风险。在之前的工作中，我们发现了一类新的c-Met拮抗剂（先导化合物ang797），它们在c-Met的atp结合位点竞争，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也靶向另一种受体酪氨酸激酶Tie-2， Tie-2参与血管生成，特别是维持肿瘤新生血管。在人胶质瘤原位模型中，ANG 797可减缓肿瘤生长并提高生存率。最近的研究表明，通过修饰2,4-二氨基喹唑啉支架上的取代基，可以提高ang797的活性和选择性。特别是，新制备的ANG 797类似物ANG 1490在4位上具有不同的取代基，对HGF/SF/c-Met途径的抑制活性提高了12倍，并且具有比ANG 797更好的水溶性。在初步的体内肺肿瘤研究中，其抗肿瘤活性有提高的趋势，但与ang797相比，其抗肿瘤活性没有统计学意义。该I期申请的重点是进一步优化2,4-二氨基喹唑啉支架，目的是确定更有效的c-Met/Tie-2拮抗剂，以推进临床开发。基于最近活性的显著改善，结合新类似物对体外细胞和激酶靶点以及体内肿瘤模型的抑制活性评估，额外的合成工作将集中在确定一个优化的先导物，以便在未来的SBIR 2期应用中进入临床前开发。

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.