Structure-Based Design of New LSD1/EGFRL858R/T790M Dual Inhibitors for Treating EGFR Mutant NSCLC Cancers

Epigenetic changes, such as LSD1 dysregulation, contribute to acquired resistance in EGFR mutant NSCLCs and reduce the effectiveness of current therapeutics. To address the challenges, we herein reported the structure-based design of new LSD1/EGFR dual inhibitors, of which ZJY-54 represents the shortlisted lead compound with high potency, selectivity, and unique dual modes of action (namely irreversibly binding to EGFR but reversibly binding to LSD1). ZJY-54 effectively inhibited growth in both parent- and TKI-resistant NSCLC cells. In H1975 cells, ZJY-54 induced accumulation of H3K4me2 and H3K9me2, as well as inhibited phosphorylation of EGFR signaling. ZJY-54 showed favorable PK profiles and effectively inhibited tumor growth in the H1975 xenograft model. ZJY-54 represents the best-in-class LSD1/EGFR dual inhibitor and warrants further preclinical development for treating NSCLCs. These findings highlight the therapeutic potential of LSD1/EGFR dual inhibitors in drug-resistant cancers where EGFR and LSD1 were dysregulated.