Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of L

Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1
Isuru R. Kumarasinghe and Patrick M. Woster, ACS Med. Chem. Lett., 2013, Just Accepted Manuscript,  DOI: 10.1021/ml4002997           Publication Date (Web): November 8, 2013                                       Copyright © 2013 American Chemical Society

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; Ki 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.