EGFR^C797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging “unmet clinical need” for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFR^C797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR^{19D/T790M/C797S} cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFR^T790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFR^C797S inhibitors as anticancer drugs.

中文翻译：

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JND3229作为具有体内单药功效的新型EGFR ^C797S突变抑制剂的发现

EGFR ^C797S突变诱导对第三代EGFR抑制剂药物的耐药性^是非小细胞肺癌患者的新兴“未满足临床需求”。嘧啶并嘧啶酮衍生物JND3229被鉴定为新型的高效EGFR ^C797S抑制剂，具有一位nM效能。在BaF3 / EGFR ^{19D / T790M / C797S}细胞的异种移植小鼠模型中，它还表现出良好的体外和体内单药抗癌功效。还确定了高分辨率的X射线晶体结构，以阐明JND3229与EGFR ^{T790M / C797S}之间的相互作用。我们的研究为新一代EGFR ^C797S抑制剂作为抗癌药物的未来开发提供了重要的结构和化学基础。