Epidermal growth factor receptor (EGFR)-targeted therapy is used to treat EGFR mutation-induced non-small cell lung cancer (NSCLC). However, its efficacy does not last beyond a certain period due to the development of primary and secondary resistance. First and second-generation inhibitors (e.g., gefitinib, erlotinib, and afatinib) induce EGFR T790M mutations, while third-generation inhibitors (e.g., osimertinib) induce C797S as a major target resistance mutation. Therefore, the C797S mutation is being actively researched. In this study, we investigated the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against the C797S mutation. We identified a compound 13k that displayed nanomolar potency and high selectivity. Moreover, we used a triple mutant xenograft mouse model to evaluate the in vivo efficacy of 13k in inhibiting EGFR C797S, which demonstrated exceptional profiles and satisfactory EGFR C797S inhibition efficacy. Based on its excellent in vitro and in vivo profiles, compound 13k can be considered a promising candidate for treating EGFR C797S mutations.

表皮生长因子受体（EGFR）靶向治疗用于治疗EGFR突变诱导的非小细胞肺癌（NSCLC）。然而，由于原发性和继发性耐药性的产生，其疗效不会持续超过一定时间。第一代和第二代抑制剂（例如吉非替尼、厄洛替尼和阿法替尼）诱导EGFR T790M突变，而第三代抑制剂（例如奥希替尼）诱导C797S作为主要靶点耐药突变。因此，C797S突变正在积极研究。在这项研究中，我们研究了几种合成化合物作为第四代 C797S 突变抑制剂的结构-活性关系。我们鉴定出一种具有纳摩尔效力和高选择性的化合物13k 。此外，我们使用三重突变异种移植小鼠模型来评估13k抑制 EGFR C797S的体内功效基于其优异的体外和体内特性，化合物13k可以被认为是治疗 EGFR C797S 突变的有前途的候选药物。