Work

Discovery of a Potent Lysine‐Specific Histone Demethylase‐1 (LSD‐1) Inhibitor for Cancer Treatment via Machine Learning, Molecular Modeling, and In Vitro Validation

Year: 2025

Type: article

Abstract: The discovery of potent lysine‐specific histone demethylase 1 (LSD‐1) inhibitors is of significant importance in cancer therapy, as LSD‐1 overexpression contributes to tumour progression and malignancy through the regulation of gene expression. We employed an integrated strategy that combined machine learning‐based virtual screening, bioassay validation, and ligand–target interaction analysis. Virtual screening identified 29 candidate compounds, of which 17 demonstrated micromolar‐level enzymatic inhibition in experimental assays. Among them, compound L01 showed strong potential as an LSD‐1 inhibitor, exhibiting significant antileukemic activity ( IC 50 = 24 µM) and confirmed binding to LSD‐1 in Kasumi‐1 cells. MST and SPR analysis confirmed the direct binding between L01 and LSD‐1 inferred from our in vitro studies. Molecular docking and molecular dynamics simulations further supported the interaction, revealing a binding affinity of L01 comparable to that of the well‐characterised reversible inhibitor SP‐2577. ADMET analysis revealed that L01 possesses excellent Caco‐2 permeability and high target specificity; however, its moderate drug‐likeness and potential toxicity issues underscore the need for further optimisation. Through computational modelling and experimental validation, our study identifies L01 as a promising LSD‐1 inhibitor with strong potential for optimisation to improve bioavailability and safety in cancer therapy.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.202501379