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-EGFR^{L858R/T790M/C797S} and Ba/F3-EGFR^{Del19/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-EGFR^{L858R/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-EGFR^{L858R/T790M/C797S} cells at the concentration of 0.8 μM and no obvious cell cycle arrest was found.

Keywords: Allosteric site; Aminopyrimidine; EGFR; Inhibitors; NSCLC.