The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC₅₀ values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (-)-4i induced cell Apoptosis and reduced phosphorylation of EGFR and Akt in a dose-dependent manner. Furthermore, (-)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t_1/2 = 1.12 h) of (-)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (-)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (-)-4i warrants further investigation in Non-Small cell lung Cancer (NSCLC) therapy.