Abstract Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797S inhibitors. One of the most potent compound 6i potently suppressed EGFRL858R/T790M/C797S kinase with an IC50 value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutants with IC50 values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

中文翻译：

---

2-Oxo-3,4-dihydropyrimido [4，5-d]嘧啶作为EGFR C797S（Cys797至Ser797）突变体的新可逆抑制剂

摘要进行了JND3229的广泛的构效关系研究，以产生一系列新的可逆的2-oxo-3,4-二氢嘧啶基[4,5-d]嘧啶特权支架作为EGFRC797S抑制剂。最有效的化合物6i之一有效抑制EGFRL858R / T790M / C797S激酶，IC50值为3.1 nmol / L，并抑制带有EGFRL858R / T790M / C797S和EGFR19D / T790M / C797S突变体的BaF3细胞的增殖，IC50值为290 nmol / L和316 nmol / L。此外，6i剂量依赖性地诱导了BaF3细胞中EGFRL858R / T790M / C797S和EGFR19D / T790M / C797S磷酸化的抑制。化合物6i可以作为有前途的先导化合物，用于进一步发现克服非小细胞肺癌（NSCLC）患者获得性耐药的药物。