Discovery of highly potent and novel LSD1 inhibitors for the treatment of acute myeloid leukemia: structure-based virtual screening, molecular dynamics simulation, and biological evaluation.

ABSTRACT: Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with a significant unmet clinical need for new therapeutic agents. Lysine-specific demethylase 1 (LSD1), a key regulator of leukemia stem cell self-renewal, has emerged as a promising epigenetic target for AML treatment. Herein, we employed an innovative multi-step integrated screening protocol, encompassing pharmacophore modeling, docking screening, molecular dynamics simulation, and biological evaluation, to identify novel LSD1 inhibitors. This comprehensive approach led to the discovery of six potent LSD1 inhibitors (we named these inhibitors LTMs 1-6), with LTM-1 exhibiting the most pronounced inhibitory effects on LSD1 (IC₅₀ = 2.11 ± 0.14 nM) and the highest selectivity for LSD1 over LSD2 (>2370-fo

SUBMITTER: Hong Y 

PROVIDER: S-EPMC11903733 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature