Modification of osimertinib to discover new potent EGFR-TK inhibitors.

The EGFR mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFR-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFR TK and EGFR TK with IC values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFR) and KC-0122 (BaF3-EGFR) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFR-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmR mutation.