新型c-Met抑制剂的设计、合成和抗肿瘤活性研究

The receptor tyrosine kinase c-Met is a new drug target for anticancer agents, c-Met inhibitor could inhibit proliferation of cancer cells and metastasis of various cancers. They remain active on multi-drug resistence cancers with less toxicixity. First, according to binding mode of c-Met and its inhibitor, an conbination approach of traditional medicinal chemistry and modern drug design techniques is applied to design new c-Met inhibitors. Then, the designed molecules are synthesized either by employing target-oriented synthetic strategy or by other high efficient synthetic methods. Next, these compounds are assayed for their activities at molecular, cellular, and animal levels; and those which are active in animal modes are evaluated on their druggability, such as their pharmcokinetic properties and toxicity profiles.Finally, the privilige molecules are selected to explore their mechanism of action. In our previous work, we have designed and synthesized a group of 77 derivatives with various scaffolds, some of which showed high potency both in intro and in vivo. The active derivatives Simm530和DW-07-559 showed excellent in vitro and in vivo activities, their activities are comparable to that of JNJ-38877605, but they are less toxic. Therefore, contiuation of this work would be expected to develop the new anticancer drug with better therapeutic profiles.

酪氨酸激酶c-Met是抗肿瘤药物的新靶点，c-Met抑制剂能抑制肿瘤的增殖和转移，对多种机制引起的耐药肿瘤有效并且毒性小。根据c-Met和其抑制剂的结合模式，结合经典药物设计和现代设计方法，设计结构新颖的c-Met抑制剂。采用定向合成和及其它高效化合物制备技术，合成设计的衍生物。然后采用分子水平、细胞水平和动物水平对合成的衍生物进行活性评价。对动物水平有效的化合物进行包括初步药代和初步毒理的成药性评价。最后对成药性好的衍生物进行作用机制研究，为c-Met抑制剂的研发奠定基础。在前期工作中，我们已设计合成77个结构新颖的衍生物，发现了一些高活性的衍生物，其中Sim530和DW-07-559在体内外均显示良好的抗肿瘤作用，活性和强生公司的临床试验药物JNJ-38877605相当，但毒性低。因此，继续开展本项目研究，将有望发现更有效的抗肿瘤药物。

随着抗肿瘤药物研究的飞速发展，针对分子靶点的抗肿瘤药物研发逐渐取代传统的细胞毒药物研发，成为当今抗肿瘤药物研究开发的重要方向。本研究主要针对c-Met 为靶点，综合药物设计、药物合成、药理活性研究和早期毒理药代研究等多个新药研究技术，研究开发了高效、低毒并具有良好代谢性质的新型c-Met 抑制剂类靶点抗肿瘤候选药物。