Discovery of a Potent Lysine-Specific Histone Demethylase-1 (LSD-1) Inhibitor for Cancer Treatment via Machine...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Oncology

Background:

• Lysine-specific histone demethylase 1 (LSD-1) overexpression is linked to cancer progression and malignancy.
• Targeting LSD-1 offers a therapeutic strategy for cancer treatment.

Purpose of the Study:

• To discover and validate novel inhibitors of LSD-1 using an integrated computational and experimental approach.
• To identify a lead compound for potential optimization in cancer therapy.

Main Methods:

• Machine learning-based virtual screening to identify candidate compounds.
• In vitro enzymatic assays and biophysical methods (MST, SPR) for bioassay validation and ligand-target interaction analysis.
• Molecular docking, molecular dynamics simulations, and ADMET analysis for computational validation.

Main Results:

• Virtual screening identified 29 candidates; 17 showed micromolar inhibition of LSD-1.
• Compound L01 demonstrated significant antileukemic activity (IC50 = 24 µM) and direct binding to LSD-1.
• L01 exhibited favorable Caco-2 permeability and target specificity, with binding affinity comparable to SP-2577, but requires further optimization for drug-likeness and toxicity.

Conclusions:

• Compound L01 is a promising LSD-1 inhibitor with demonstrated antileukemic potential.
• Further structural optimization of L01 is warranted to improve bioavailability and safety for cancer therapy applications.