Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M–mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type. Furthermore, crystal structure analysis suggested that CH7233163 is a noncovalent ATP-competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib-resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

中文翻译：

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CH7233163克服了对奥希替尼耐药的EGFR-Del19/T790M/C797S突变

奥希替尼是唯一能够克服 EGFR-T790M 突变的 NSCLC 的 EGFR 酪氨酸激酶抑制剂 (TKI)，但已报道了对奥希替尼耐药的 EGFR 三重突变（Del19/T790M/C797S 或 L858R/T790M/C797S）。尽管已经确定了可能克服 L858R/T790M/C797S 的变构 EGFR TKI（例如，EAI-045），但没有针对 Del19/T790M/C797S 的有效抑制剂。在这项研究中，我们确定 CH7233163 具有克服 EGFR-Del19/T790M/C797S 的潜力。CH7233163 在体外和体内均显示出针对 EGFR-Del19/T790M/C797S 的有效抗肿瘤活性。除了 EGFR-Del19/T790M/C797S，表征分析表明 CH7233163 比野生型更选择性地抑制各种类型的 EGFR 突变体（例如，L858R/T790M/C797S、L858R/T790M、Del19/T790M、Del19 和 L858R） . 此外，晶体结构分析表明，CH7233163 是 EGFR-Del19/T790M/C797S 的非共价 ATP 竞争性抑制剂，它利用与 EGFR 的 αC-helix-in 构象的多重相互作用来实现有效的抑制活性和突变选择性。因此，我们得出结论，CH7233163 是对奥希替尼耐药患者的潜在有效疗法，特别是在 EGFR-Del19/T790M/C797S 的情况下。