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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 ?M. Compound 9 was a potent LSD1 inhibitor (IC50 2.1 ?M; 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.

SUBMITTER: Kumarasinghe IR

PROVIDER: S-EPMC4027766 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of novel cyclic Peptide inhibitors of lysine-specific demethylase 1.

Kumarasinghe Isuru R IR Woster Patrick M PM

ACS medicinal chemistry letters 20131108 1

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 pept ...[more]

PMID: 24883177

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