表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs) 在非小细胞肺癌（NSCLC）冶疗中发挥了里程碑式作用，但随着临床的广泛应用，耐药现象成为新的瓶颈。研究显示，c-Met抑制剂联合吉非替尼治疗EGFR-TKI耐药的NSCLC取得较好疗效。为了解决其耐药问题，开发具有抗耐药性c-Met/EGFR双重抑制剂意义重大。在本项目中，我们在前期发现的小分子c-Met和EGFR抑制剂的基础上，运用生物电子等排、拼合等原理，进行化合物的设计合成、活性评价和构效关系研究。通过分析已有化合物的构效关系，结合其与c-Met和EGFR 蛋白对接结果，对喹啉母核及“5-原子规则”侧链进行改造，设计新型c-Met/EGFR双重抑制剂组合分子库。通过进一步计算机虚拟筛选、化学合成, 应用分子、细胞和动物模型对化合物进行活性评价，开发出体内外活性显著、毒性小、具有抗耐药性的c-Met/EGFR双重抑制剂。

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play a milestone role in the treatment of non small cell lung cancer(NSCLC). However, with the wide application inclinical, the phenomenon of drug resistance has become a new difficulty. The research shown that the clinical result was satisfactory through combination of c-Met inhibitors and gefitinib for treating NSCLC that resistant to EGFR-TKIs. In order to solve the problem of drug resistance, it's definitely meaningful for developing dual c-Met/EGFR inhibitors for overcoming drug resistance. In continuation of our previous research of c-Met or EGFR inhibitors, further modification, synthesis, biological evaluation and SARs studies of new compounds will be carried out on the base of hybridization principle and bioisosterism in this project. Through analysising the SARs and the results of docking with c-Met or EGFR kinases, a new compound-library of dual c-Met/EGFR inhibitors will be built with the structural modifications at nucleus of quinoline moiety and the side-chains of "five-atoms rule". After virtual screening, chemical synthesis, and evaluting activity at different levels, a series of novel dual c-Met/EGFR inhibitors for overcoming drug resistance were achieved, expected to possess excellent in vitro/in vivo anti-tumor activity and low toxicity.