Both the first‐generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second‐generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) afatinib have significantly improved the survival of non‐small‐cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFR^T790M mutation leads to the clinically acquired resistance to the first‐ and second‐generation EGFR‐TKIs drugs. A number of the third‐generation wild‐type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFR^T790M. More recently, a tertiary EGFR^C797S mutation was reported as the dominant resistance mechanism to the third‐generation irreversible inhibitors. It is highly desirable to develop the fourth‐generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third‐ and fourth‐generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFR^C797S mutation.

中文翻译：

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针对NSCLC中的EGFRL858R / T790M和EGFRL858R / T790M / C797S耐药性突变：药物化学的最新进展

第一代可逆表皮生长因子受体（EGFR）抑制剂吉非替尼和厄洛替尼以及第二代共价表皮生长因子受体酪氨酸激酶抑制剂（afatinib）均显着提高了非小细胞肺癌的生存率（ NSCLC）激活EGFR突变的患者。但是，继发性EGFR ^T790M突变导致临床上获得的对第一代和第二代EGFR-TKIs药物的耐药性。已经开发了许多第三代野生型节约型EGFR抑制剂，例如WZ4002，CO1686，AZD9291，HM61713，EGF816，ASP8173和PF0674775，其中AZD9291已被美国FDA批准用于NSCLC的治疗。 EGFR ^T790M患者。最近，第三EGFR据报道，^C797S突变是对第三代不可逆抑制剂的主要抗性机制。迫切需要开发第四代EGFR抑制剂。这篇综述总结了第三代和第四代EGFR抑制剂获得性耐药的机制和最新的药物化学进展，并特别关注了对抗第三级EGFR ^C797S突变的变构和可逆抑制剂。