EP-0093I/EP0093A

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.