肺癌是导致死亡率最高的常见癌症类型，其中EGFR激酶突变是导致肺癌的主要原因之一，最新临床数据显示含有T790M/C797S的EGFR致癌性突变已经对新一代靶向抑制剂AZD9291产生耐药性，因此针对新突变研发新一代靶向抑制剂迫在眉睫。最新研究发现：获得FDA批准的ALK靶向抑制剂Brigatinib具有克服EGFR新一代耐药性突变的潜力。我们前期通过X-射线晶体学手段首次解析了一系列Brigatinib与EGFR、ALK的耐药性突变及野生型的复合物结构，并首次发现了激酶中P-loop与药物结合的特殊构象。基于Brigatinib的成药安全性以及EGFR、ALK中P-loop氨基酸序列的差异性，我们将采用结构药理学的手段对Brigatinib进行精准定向设计及优化，有针对性的提高药物对T790M/C797S的亲和力与选择性，尝试研发新一代抗肺癌EGFR T790M/C797S靶向抑制剂。

Lung cancer is a common type of cancer with the highest mortality, and EGFR kinase mutation is one of the main causes of lung cancer. The latest clinical data show that the EGFR mutation containing T790M/C797S has developed resistance to the new generation targeted inhibitor AZD9291, so it is urgent to develop a new generation targeted inhibitor. Recent studies have found that Brigatinib, an FDA approved ALK targeted inhibitor, has the potential to overcome the new generation resistant EGFR mutations. In our preliminary studies, we have obtained a series of complex structure of Brigatinib with EGFR and ALK through X-ray crystallography. Due to the interaction with Brigatinib, the P-loop of these kinases in the complex structures adopt unique conformations that are discovered for the first time. Based on the safety of Brigatinib and the differences of p-loop amino acid sequences in EGFR and ALK, we plan to optimize Brigatinib in a precise and targeted manner with the guide of structural pharmacology. In this project, our study will improve the affinity and selectivity of drugs for T790M/C797S and try to develop a new generation anti-lung cancer drugs targeting EGFR T790M/C797S.