Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1- Sickle Cell Disease


 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. For example, cyclic peptide 9 inhibits LSD1 in vitro with a Ki value of 385 nM and is significantly more stable than the corresponding linear peptide. The series of peptides are being developing as antitumor agents and to be used as fetal hemoglobin inducers for sickle cell disease (SCD). These cyclic peptides represent important lead structures for the design of peptidomimetic inhibitors of flavin-dependent histone demethylases.


These peptides have been shown to possess low cytotoxicity in K562 cells (data not shown), and induce the fetal hemoglobin gene  gamma-globin up to 10-fold, which is 5x greater than the current therapy hydroxyurea.


Overview: Sickle cell disease (SCD) is the most common inherited blood disorder in the US.  Affected patients are at risk of multi-system complications, significant morbidity and early mortality. Persons with SCD that have increased % of fetal hemoglobin (HbF) have less pain and fewer episodes of acute chest syndrome along with a decreased risk of mortality.  The only current FDA approved fetal hemoglobin inducer, Hydroxyurea, remains highly underutilized due (in part) to the risk of complications. The discovery of a new fetal hemoglobin stimulator could potentially revolutionize the care of affected patients. Epigenetic modification is one possible mechanism.  Recent studies with the lysine specific demethylase (LSD-1) inhibitors, including tranylcypromine (TCP) show promising results.  Unfortunately, TCP also has effects on monoamine oxidase and thus significant unwanted side effects. Developing a molecule with high specificity for LSD-1, low cross reactivity and negligible toxicity would increase effect and reduce unwanted side effects.


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. "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:       P1410a


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