摘要Histone lysine-specific demethylase 1(LSD1)is overexpressed in various solid and hematological tumors,suggesting its potential as a therapeutic target,but there are currently no LSD1 inhibitors available on the market.In this study we employed a computer-guided approach to identify novel LSD1/EGFR dual inhibitors as a potential therapeutic agent for non-small cell lung cancer.Through a multi-stage virtual screening approach,we found L-1 and L-6,two compounds with unique scaffolds that effectively inhibit LSD1 with IC50 values of 6.24 and 9.26 μM,respectively.Using molecular similarity-based screening,48 analogs of L-1 and L-6 were retrieved from ChemDiv library,18 analogs were selected for biological activity analysis.Eight compounds showed weaker inhibitory activity against LSD1,with IC50 values of 19.79-35.70 μM.Moreover,L-1,L-6,and two analogs of L-6(D-14 and D-16)were found to inhibit triple-mutant EGFR(L858R/T790M/C797S)with potencies ranging from 5.01 to 86.70 μM,and to inhibit double-mutant EGFR(T790M/L858R)with potencies ranging from 2.06 to 64.36 μM.In BaF3 cells that stably express EGFR(L858R/T790M/C797S),the inhibitory activity of L-1,L-6,D-14 and D-16 ranged from 2.72 to 8.99 μM.L-1 that shows the highest biological activity across BaF3 cell,mutant EGFR kinase and LSD1 assays due to its dual targeting of LSD1/EGFR,emerges as a promising lead compound for non-small cell lung cancer treatment.This study demonstrates that L-1 efficiently inhibits lung cancer growth in vitro and in vivo,suggesting it as a potential lead for non-small cell lung cancer treatment,highlighting the utility of virtual screening methods in discovering multi-target inhibitors and strategies for other diseases.