c-Met激酶是目前抗肿瘤药物研究的热点靶标之一。而且HGF/c-Met信号转导通路与其他激酶抑制剂的耐药性，放疗后的转移和复发，以及细胞毒类抗肿瘤药物的耐药性密切相关。c-Met的突变等原因也导致了其抑制剂自身耐药性的发生。因此，开发新型尤其是具有突变型抑制活性的c-Met抑制剂对解决耐药性问题至关重要。本项目基于前期获得的嘧啶并吲哚类c-Met抑制剂，针对c-Met双磷酸化后新出现的结合口袋，运用基于片段的药物设计方法，对母核进行开环得到具有突变型抑制活性的新型c-Met抑制剂。初步活性结果确证了设计思路的合理性。实验还发现该类抑制剂具有c-Met高选择性，可降低毒副作用。本项目将继续提高对c-Met突变型的抑制活性，探索解决耐药性问题。同时，从分子、细胞和动物水平上评价目标化合物，初步阐明其抗肿瘤作用机制，总结构效关系，进一步优化结构，为最终获得具有自主知识产权的抗肿瘤新药打下基础。

c-Met is one of the promising targets for developing antitumor agents due to its central role in tumorigenesis and metastasis, and its excessive expression, abnormal activation and mutation in various types of cancers. It was also reported to be closely associated with the resistance to certain kinase inhibitors and cytotoxic antitumor agents, and even with the cancer metastasis and relapse after radiotherapy. Besides, drug resistance to c-Met inhibitors was also found because of its various mutations. Therefore, it makes significant sense for solving the resistance to anticancer therapies and improving curative effects by developing novel c-Met inhibitors, especially those against c-Met mutations. A novel series of c-Met inhibitors with inhibitory activity against mutated c-Met were obtained through structure optimization of our novel c-Met inhibitors based on the scaffold of 5H-pyrimido[5,4-b]indole using fragment-based drug design approaches. This series of inhibitors have an absolutely novel binding mode as they extend into the new pocket emerged after biophosphorylation. The primary biological activity confirmed the rationality of methods for drug design. High c-Met selectivity was also found with these compounds in the kinase selectivity assays. This project will continue the study of these novel c-Met inhibitors, improving the activity against the mutated types and keeping the selectivity, to explore the solution of drug resistance due to anticancer therapies. Meanwhile, the novel compounds will be assessed at the level of kinase, cell and animal model to clarify their primary antitumor mechanism. Structure-activity relationship will be summarized for further structure optimization. Overall, this project will be a solid foundation for developing novel antitumor drugs of independent intellectual property rights.