title: Synthesis and evaluation of novel cyclic Peptide inhibitors of lysine-specific demethylase 1.
abstract: Lysine specific demethylase 1 (LSD1) selectively removes methyl groups from mono- and dimethylated histone 3 lysine 4 (H3K4), resulting in gene silencing. LSD1 is overexpressed in many human cancers, resulting in aberrant silencing of tumor suppressor genes. Thus, LSD1 is a validated target for the discovery of antitumor agents. Using a ligand-based approach, we designed and synthesized a series of cyclic and linear peptides that are effective inhibitors of LSD1. Linear peptide 7 and cyclic peptide 9 inhibited LSD1 in vitro by 91 and 94%, respectively, at a concentration of 10 μM. Compound 9 was a potent LSD1 inhibitor (IC50 2.1 μM; K i 385 nM) and had moderate antitumor activity in the MCF-7 and Calu-6 cell lines in vitro. Importantly, 9 is significantly more stable to hydrolysis in rat plasma than the linear analogue 7. The cyclic peptides described herein represent important lead structures in the search for inhibitors of flavin-dependent histone demethylases.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina , 70 President Street, Charleston, South Carolina 29425, United States.
authors.forename: Isuru R
authors.initials: IR
authors.lastname: Kumarasinghe
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina , 70 President Street, Charleston, South Carolina 29425, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
keywords: Chromatin architecture; KDM inhibitors; chromatin remodeling; cyclic peptide; histone; histone 3 lysine 4; lysine specific demethylase