LSD1 Protein Inhibitors as Fetal Hemoglobin Inducers for Sickle Cell Disease


 Technology: Researchers at MUSC have identified several potential inhibitors of lysine-specific demethylase 1 (LSD1) utilizing a virtual screen, and found compounds that fit the LSD1 active site in silico. Researchers have synthesized these molecules and evaluated them as LSD1 inhibitors, and several compounds inhibit the enzyme with Ki values in the mid-to upper nanomolar range. The series of compounds are new chemical entities and are being developed by structural modification into lead compounds with the goal of developing them as antitumor agents as well as exploring them for sickle cell disease with high selectivity and low in vivo toxicity to be used as fetal hemoglobin inducers in sickle cell disease. Compound M2 at 500 nM promotes a 12 fold increase in fetal hemoglobin, which is 6x greater than the current therapy, hydroxyurea.


Fold increase in mRNA for gamma globin from RT-qPCR. All concentrations in uM

Experimental compounds were compared to DMSO, 10 uM hemin and 200 uM HU

Panel A: Fold increase in gamma globin mRNA in the presence of hemin and experimental compounds at varying concentrations

Panel C: Fold increase in gamma globin mRNA in the presence of hemin and new experimental compounds.

* Indicates significance compared to HU using one way ANOVA


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 with increased % of fetal hemoglobin (Hb F) have a less pain and fewer decreased number of pain crises and episodes of acute chest episodes 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, neurological disorders, and sickle cell disease.

Advantages: Increased specificity for LSD1, which could reduce off-target effects, and improved pharmacokinetic parameters. 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: Sickle cell disease, hemoglobin, cancer, epigenetics, LSD1, tumor suppressor genes, DNA, histones, enzyme inhibitors.


Publication: Kutz, Craig J., et al. "3, 5-Diamino-1, 2, 4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors." MedChemComm (2014).


Inventors: Patrick Woster & Craig Kutz

Patent Status: US Patent 10,118,903

MUSC-FRD Technology ID: P1412a


Patent Information:
For Information, Contact:
Scott Davis
Associate Director, Licensing
MUSC Foundation for Research Development
Patrick Woster
Craig Kutz
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