肺癌是导致死亡数最高的常见癌症类型，EGFR 激酶突变是导致肺癌的主要原因之一。EGFR靶向性治疗中肿瘤细胞会产生耐药性而导致癌症复发。约50%的复发病例中耐药性是由于EGFR产生第二个突变T790M而引起，因此开发新一代靶向性治疗T790M的药物是本研究领域一个十分重要和紧迫的任务。我们的前期研究已阐明T790M导致耐药的复杂机理（发表于PNAS），并据此提出了克服T790M耐药的三种策略。我们依据第一种策略研发新药先导化合物的工作已发表于Nature，但该先导化合物还具有一些内在问题。现有药物化学实验室依据我们提出的第二种策略研发了一批小分子抑制剂，本项目将测定这批抑制剂与T790M系列突变体的复合物晶体结构，并用基于三维结构的合理药物设计方法尝试对其进行改进设计。

Lung cancer is a frequently seen cancer type and the leading cause of cancer deaths. Mutations in the EGFR kinase domain are one of the major causes of this disease. During EGFR-targeted chemotherapy, tumor cells develop resistance to the drugs which result in relapse of the disease. In about 50% of the relapsed cases, drug-resistance is caused by T790M, a secondary mutation in EGFR. Therefore to develop new drugs targeting EGFR T790M is an important and urgent task in the field. Our previous work has revealed the complicated mechanism by which T790M causes drug-resistance (this work was published in PNAS), and based on this study we have proposed three strategies for developing new drugs to kill this mutation. Our report of the efforts to develop new drug leading compounds according to the first strategy has been published in Nature, but the compounds we discovered in this study have some intrinsic weakness. Recently, a medicinal chemistry lab designed a series of small molecule inhibitors according to the second strategy proposed by us. In this project we propose to solve the crystal structures of EGFR T790M mutants in complex with these inhibitors, and to optimize them using the method of three-dimensional structure directed rational drug design.