Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC.

ABSTRACT

Starting from the binding mode of allosteric EGFR inhibitor JBJ-04-125-02 and the key pharmacophore of the third-generation EGFR inhibitors, we designed and synthesized a novel series of EGFR inhibitors, represented by (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide (6q). Docking study demonstrated that top compound 6q spanned orthosteric and allosteric sites of EGFR, and formed three key H-bonds with the residues Asp855, Lys745, and Met793 located in two sites. Biological evaluation indicated that compound 6q showed potential inhibitory activity against Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFRDel19/T790M/C797S cells, with IC50 values of 0.42 µM and 0.41 µM, respectively. Furthermore, compound 6q showed excellent activity against mutant NSCLC cell line NCI-H1975-EGFRL858R/T790M/C797S cells, with IC50 value of 0.82 µM which was superior to that of osimertinib (IC50 = 2.94 µM), JBJ-04-125-02 (IC50 = 3.66 µM), and coadministration of JBJ-04-125-02 and osimertinib (IC50 = 1.25 µM). Cell cycle arrest and cell apoptosis assay indicated that compound 6q could promote apoptosis of NCI-H1975-EGFRL858R/T790M/C797S cells at the concentration of 0.8 µM and no obvious cell cycle arrest was found.