抗肿瘤新生血管生成是一个备受关注的肿瘤治疗领域，目前临床上使用的肿瘤新生血管抑制剂虽然具有显著的肿瘤治疗作用，但耐药、毒副作用大等问题很大程度地限制了该类药物的广泛应用。我们在前期研究中发现，具有全新结构的小分子化合物Z1506能够显著抑制VEGFR-2活性，有效抑制肿瘤新生血管生成。Z1506对肝癌和胃癌裸小鼠移植瘤具有非常显著的实验治疗作用，对肝癌的治愈率甚至达到80％，而且毒副作用明显小于临床抗肝癌靶向药物索拉菲尼，显示了很好的应用前景。进一步研究发现，Z1506还对Aurora激酶具有明显的抑制作用，从而诱导细胞发生周期阻滞，有效抑制肿瘤细胞增殖。本项目将在此基础上，系统评价Z1506的体内外抗肿瘤活性，明确抑制肿瘤新生血管生成和Aurora激酶所产生的协同效应是Z1506抗肿瘤活性发挥的重要环节，寻找其中发挥关键作用的蛋白和信号通路，为抗肿瘤药物的研发提供全新的思路。

Anti-angiogenesis has been considered as a promising approach for anti-cancer therapy since 1970s. Although some VEGFR signal targeted drugs have been approved for clinical use, their utility is limited by associated toxicities, low efficiency or resistance to such therapy. By evaluating the inhibitory effect of a novel series of Pyrazolobenzodiazepine derivatives on VEGFR-2 activity, we found compound Z1506 exhibited the highest VEGFR-2 inhibitory potency, thus inhibiting tumor angiogenesis efficiently. The in vivo anti-tumor efficacy of Z1506 was evaluated on hepatocarcinoma and gastric cancer xenografts in a parallel comparison with another multikinase inhibitor sorafenib. Z1506 demonstrated superior efficacy and low toxicity profile over sorafenib in both test models with 80% tumor growth inhibition and tumor regression in hepatocarcinoma xenografts. Intriguingly, Z1506 abrogated the catalytic activities of Aurora kinases and led to an obvious G2/M phase arrest, thus suppressed the proliferation of tumor cells in vitro. Here, we will further evaluate the anti-tumor effect of Z1506 in vitro and in vivo systematically, demonstrate the synergistic effects between anti-angiogenesis and Aurora kinases inhibition activity of Z1506, investigate the potential targets that play important roles in the anti-tumor effect of Z1506. We hope that our study will provide the molecular theoretical basis for combination of VEGFR and Aurora inhibitors in clinic and the development of novel small molecular inhibitors targeting these two kinase families.