Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors

The EGFR^C797S 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^C797S-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFR^{Del19/T790M/C797S} TK and EGFR^{L858R/T790M/C797S} TK with IC₅₀ values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFR^{Del19/T790M/C797S}) and KC-0122 (BaF3-EGFR^{L858R/T790M/C797S}) 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^C797S-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmR^C797S mutation.

Antitumor effect; C797S mutation; EGFR-TK inhibitor; Phenylamino-pyrimidines; Synthesis.