2 Oxo 3,4 dihydropyrimido[4,5 d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant
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.