Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1‑Selective Inactivators

Inhibition
of lysine-specific demethylase 1 (LSD1), a flavin-dependent
histone demethylase, has recently emerged as a new strategy for treating
cancer and other diseases. LSD1 interacts physically with SNAIL1,
a member of the SNAIL/SCRATCH family of transcription factors. This
study describes the discovery of SNAIL1 peptide-based inactivators
of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl
amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory
activity in enzyme assays. Kinetic study and mass spectrometric analysis
indicated that peptide 3 is a mechanism-based LSD1 inhibitor.
Furthermore, peptides 37 and 38, which consist
of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4
of histone H3 in HeLa cells, suggesting that they are likely to exhibit
LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this
new approach for targeting LSD1 provides a basis for development of
potent selective inhibitors and biological probes for LSD1.