非小细胞肺癌（NSCLC）是导致死亡数最高的肺癌类型，EGFR抑制剂可有效治疗NSCLC，但T790M突变常导致抑制剂产生耐药性。新一代抑制剂如WZ4002等，虽可有效逆转T790M耐药，但存在激酶选择性差和毒副作用大等缺陷。我们前期发现嘧啶类抑制剂母核与突变前后的790位残基间存在较大的距离空间差异，且EGFR T790M结合口袋右侧存在特异性的氨基酸序列和结构，相异于其他激酶。本项目中，我们拟基于WZ4002在EGFR T790M结合口袋的作用模式，并针对口袋右侧特有的空间和氨基酸序列设计并合成一类去除Michael受体的新型嘧啶[5,6-d]并杂环类高效选择性抑制剂。测试该类抑制剂的激酶抑制和选择性，表征体内外抗肿瘤活性，并通过蛋白-药物共结晶确证其与EGFR T790M的结合模式和位点。本项目将为以EGFR T790M为靶标的抗NSCLC药物研究提供新的作用位点和新型选择型抑制剂。

Non-small cell lung cancer (NSCLC) is the most common cause of death among all major types of lung cancers, which could be responded remarkably to small molecule epidermal growth factor receptor (EGFR) inhibitors. However,the T790M mutation in EGFR kinase often causes drug resistance to the inhibtiors. Currently, multiple "New-generation" EGFR inhibitors, such as WZ4002, that can overcome EGFR T790M-mediated resistance in preclinical models, but lacking kinase selectivity and giving rise to a variety of side and toxic effects. In our previous study, we found that the pyrimidine core which contained in "Third-generation" EGFR inhibitors, gave the great differences in three-dimensional space and the distance to 790 amino acid residues before and after among mutation via computer-assisted analysis. Additionally, ATP-binding sites in currently available inhibitors account for only a fraction of the ATP-binding pocket in the EGFR T790M protein and are localized in the right side within the cavity of the whole ATP-binding pocket, it is different from other RTKs. In this project, based on this finding and the amino acid sequence right side of ATP-binding pocket, we plan to design and synthesize a novel series of potent Pyrimido[5,6-d]heterocyclic derivatives with deleting Micheal receptor group as selective EGFR T790M inhibitors. Meanwhile, several inhibitors will be chosen to test the inhibition and selectivity between EGFR T790M and other RTKs, investigating the anti-tumor activity in vitro and in vivo, confirmiung the ligand binding mode and the sites of the EGFR T790M protein through the crystallization of protein-ligand complexes. This project will provide new sites of action and selective and efficient inhibitors targeting EGFR T790M in NSCLC.