Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1 (LSD1)


Technology: Researchers at MUSC have used a ligand-based approach to design and synthesize a series of cyclic peptides that are effective inhibitors of LSD1, and have greater stability to proteolytic degradation than their linear homologues.  Cyclic peptide 9 inhibits LSD1 in vitro with a Ki value of 385 nM, and has antitumor activity in MCF-7 and Calu-6 cell lines in vitro. Importantly, compound 9 is significantly more stable to hydrolysis in a rat plasma degradation study than the corresponding linear analogue 7. These cyclic peptides represent important lead structures for the design of peptidomimetic inhibitors of flavin-dependent histone demethylases.



Overview: Histone proteins interact with double-stranded DNA to form nucleosomes, and feature lysine-rich histone tails that protrude from the nucleosomal DNA strand. These lysine-rich histone tails provide a site for post-translational modification of chromatin, allowing for alteration of higher order nucleosome structure and precise control of gene expression.  LSD1 is a histone demethlyase that catalyzes the oxidative demethylation of specific histone lysines, and is overexpressed in a number of cancer cell lines (neuroblastoma, retinoblastoma, prostate cancer, breast cancer, lung cancer, and bladder cancer), which silences genes that code for tumor suppressor proteins important in human cancer. Thus, LSD1 has emerged as an important target for the development of specific LSD1 inhibitors as a new class of antitumor drugs. To date, no cyclic peptides have been described as inhibitors of LSD1, and these inhibitors have potential to act as epigenetic modulators. In addition to cancer, aberrant gene silencing plays a role in other diseases such as diabetes, cardiovascular disease, and neurological disorders. Epigenetic modulators can be used to reverse aberrant gene silencing, and thus have a positive effect on the progression of these diseases.


Applications: Therapeutic agents for various cancers as well as diabetes, cardiovascular diseases, and neurological disorders.

Advantages:  Greater stability against proteolytic degradation than linear homologues of LSD1 inhibitors, and increased specificity for LSD1, which could reduce off-target effects. Also, these compounds are reversible, non-covalent inhibitors that do not depend on bioactivation, as do tranylcypromine-based inhibitors currently in clinical trials.

Key Words: Cancer, epigenetics, LSD1, peptide inhibitors, peptidomimetics, tumor suppressor genes, DNA, histones


Publications: Kumarasinghe, Isuru R., and Patrick M. Woster, “Cyclic peptide inhibitors of lysine-specific demethylase 1 with improved potency by alanine scanning mutagenesis” European Journal of Medicinal Chemistry (2018); Kumarasinghe, Isuru R., and Patrick M. Woster. "Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1." ACS Medicinal Chemistry Letters (2013).

Inventors: Patrick M. Woster & Isuru Kumarasinge
Patent Status: US Patent 9,186,391

MUSC-FRD Technology ID: P1410

Patent Information:
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Patrick Woster
Isuru Kumarasinghe
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