Discovery of YS-363 as a highly potent, selective, and orally efficacious EGFR inhibitor

The Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for EGFR-mutated NSCLC. However, long-term clinical treatment often leads to acquired drug resistance, making NSCLC refractory. Therefore, it is essential to design new EGFR inhibitors as potential drugs against NSCLC. This study reports on a novel quinazoline-based compound called YS-363 that acts as a new EGFR inhibitor. YS-363 demonstrated potent inhibition against both wild-type and L858R mutant forms of EGFR with IC50 values of 0.96 nM and 0.67 nM, respectively. Additionally, YS-363 had a reversible inhibitory effect on cellular EGFR signaling, had excellent inhibitory activity on cell proliferation and migration, and induced G0/G1 cell cycle arrest and apoptosis. In xenograft models dependent on EGFR signaling, oral administration of YS-363 substantially suppressed tumor growth by inhibiting this pathway. In summary, YS-363 is a promising selective reversible inhibitor with a novel quinazoline scaffold that can potentially develop more effective anti-lung cancer agents targeting EGFR in patients who have developed resistance to current therapies such as TKIs like gefitinib or erlotinib. •YS-363 is a newly discovered selective and orally reversible EGFR inhibitor that inhibits EGFR wt and EGFR-activating mutations kinase activities at nanomolar IC50 levels.•Different from gefitinib and erlotinib, YS-363 features the 4-indoyl quinazoline scaffold.•YS-363 inhibits the phosphorylation of EGFR as well as downstream ERK and AKT, thereby exerting an antitumor effect in vivo and in vitro.