The new N2-phenyl-N4-5-(dimethylphosphinyl)-6-quinoxalinamine pyrimidine-2,4-diamine derivatives as EGFR inhibitors to overcome C797S-mediated resistance

Abstract

A series of novel N²-phenyl-N⁴-5-(dimethylphosphinyl)-6-quinoxalinaminepyrimidine-2,4-diamine derivatives were synthesized and evaluated as potential inhibitors of EGFR C797S-mediated resistance. Notably, most of these compounds exhibited robust antiproliferative activity against Baf3-EGFR^{L858R/T790M/C797S} and Baf3-EGFR^{Del19/T790M/C797S} cancer cell lines with IC₅₀ values in the nanomolar range. Among them, compound Y9m showed the most potent inhibitory activity with IC₅₀ values as low as 8–9 nM. Mechanistic studies showed that Y9m effectively inhibited EGFR ^{L858R/T790M/C797S} and EGFR^{Del19/T790M/C797S} kinases, which modulate the phosphorylation of the EGFR signaling pathway proteins. Notably, PI3K phosphorylation in the mTOR signaling pathway decreased as compound concentration increased, which implies that Y9m enhances anti-tumor activity by blocking the phosphorylation of the dual signaling pathways. Y9m induced cell cycle arrest at the G0/G1 phase by inducing apoptosis through the inhibition of CyclinD1 expression and regulating Caspase-3 expression. In conclusion, Y9m is a promising candidate in the development of highly efficacious anticancer agents.