Discovery of novel dual-target inhibitors of LSD1/EGFR for non-small cell lung cancer therapy  

作　　者：Yu Wei Ming-ming Sun Rui-li Zhang Lin Wang Li-hong Yang Chang-liang Shan Jian-ping Lin 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,Nankai University,Tianjin,300350,China [2]Biodesign Center,Tianjin Institute of Industrial Biotechnology,Chinese Academy of Sciences,Tianjin,300308,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1030-1044,共15页中国药理学报(英文版)

基　　金：supported by grants from National Natural Science Foundation of China(81973356 to CLS);National Key R&D Program of China(2017YFC1104400 to JPL).

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 IC_(50)values of 6.24 and 9.26μM,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 IC_(50)values of 19.79–35.70μM.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 86.70μM,and to inhibit double-mutant EGFR(T790M/L858R)with potencies ranging from 2.06 to 64.36μM.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 8.99μM.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.

关 键 词：LSD1 EGFR lung cancer virtual screening INHIBITOR 

分 类 号：R734.2[医药卫生—肿瘤]