第三代选择性EGFR(T790M)不可逆抑制剂Osimertinib在2015年11月获得美国FDA批准上市。但EGFR进一步C797S点突变引发新的耐药，这是现在临床亟需解决的问题。目前针对新突变尚缺乏单独使用有效的小分子抑制剂。我们通过转变“不可逆型”到“可逆型”抑制剂的设计思路，结合化合物库筛选以及合理结构优化，成功获得了一类全新的EGFR(L858R/T790M/C797S)抑制剂。其中化合物D3003对靶标激酶的IC50值为38 nM，对稳定表达EGFR(L858R/T790M/C797S)的BaF3细胞增殖的IC50值为0.058 uM。据相关文献检索，这是目前细胞活性最强的EGFR(L858R/T790M/C797S)小分子抑制剂。本项目将以D3003为先导化合物进行系统的构效关系及体内外抗肿瘤活性研究，为克服临床Osimertinib耐药提供重要的候选化合物。

U. S. FDA granted accelerated approval to Osimertinib for the treatment of patients with metastatic EGFR (T790M) mutation-positive non-small cell lung cancer (NSCLC). However, it was reported that EGFR C797S mutation mediates resistance to Osimertinib. A few small molecules were reported to suppress the kinase activity of EGFR L858R/T790M/C797S. However, the week activity of these molecules limits their potential as a single drug for the treatment of EGFR C797S mutant NSCLC. It is highly desirable to identify novel EGFRL858R/T790M/C797S inhibitors for the unmet clinical need. We have successfully identify a series of EGFRL858R/T790M/C797S inhibitors through chemical library screening and rational structure optimization. One of the most promising compounds D3003 shows potent in vitro activity against EGFRL858R/T790M/C797S kinase as well as BaF3 cells harboring EGFRL858R/T790M/C797S with IC50 value of 38 nM and 0.058 uM, respectively. Base on the literature search, D3003 is the most potent small molecule target EGFRL858R/T790M/C797S in cells. On the basis of previous investigation, we will continue our systemic SAR study, in vitro and in vivo anti-tumor activities of D3003-like compounds. It hopes to develop drug-like candidates for the clinical test to overcome osimertinib resistance.