Description:
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.
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)
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