Mer/c-Met双靶点抑制剂的设计，合成及抗肿瘤活性评价

Mer和c-Met是肿瘤发生与发展的重要靶点，研究开发Mer/c-Met双靶点抑制剂可望同时实现两个靶点的调控，与单靶点抑制剂相比，能更高效地抑制肿瘤的发生和发展，并有效地克服肿瘤细胞的耐药性，且可避免联合用药可能引起的不良反应加重、药代动力学相互影响等，为目前抗肿瘤领域研究的前沿热点。.本项目以Mer/c-Met双靶点抑制剂为研究对象，在前期已获得的具有较好的体外活性、初步安全性及药代动力学性质的化合物HBST274基础上，结合药物构效分析及酶蛋白空腔对底物的空间及电性要求，继续探索研究该类双靶点抑制剂，通过合理的路线合成这些新化合物并进行活性测试，根据活性结果构建药效团模型，寻找与Mer/c-Met结合更好的新活性分子，目的是获得高效、低毒、且成药性较好的Mer/c-Met双靶点抑制剂。本项目可为开发Mer/c-Met双靶点抑制剂提供数据基础和理论依据，具有重要的科学意义和研究价值。

Mer and c-Met are promising novel cancer therapeutic targets, and are critical in mediating cancer cell proliferation, metastasis and invasion. The inhibition of the Mer/c-Met signaling pathway has great potential for intervention in proliferation, drug-resistance, which can avoid side effects and poor pharmacokinetic properties from combined therapy. Thus, dual inhibition of Mer/c-Met is an attractive therapeutic method for cancer therapy..According to the QSAR, the enzyme protein cavity, two series of novel dual Mer/c-Met inhibitors were designed in previous study, and compound HBST274 was found with high in vitro activity, low toxicity and good pharmacokinetic property, which provide a rationale for further investigation of the dual Mer/c-Met inhibitors and the pharmacophore model to scan new compounds with better affinity. Consequently, study on dual Mer/c-Met inhibitors to develop novel chemical entities with great activity, low toxicity and good drug ability is much more rational and of great significance.