LSD1 Protein Inhibitors as Epigenetic Modulators


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. LSD1 is overexposed in a number of human cancers (neuroblastoma, retinoblastoma, prostate, cancer, lung, and bladder), and has emerged as an important target for the development of specific inhibitors as a new class of antitumor drugs. Researchers have synthesized these molecules and evaluated them as LSD1 inhibitors.  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. These compounds are also selective for LSD1 over MAO A and B. Preliminary studies have shown that two of the compounds inhibit LSD1 and promote increases in histone lysine methylation at histone 3 lysine 4 (H3K4).

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. Investigators in both academia and the pharmaceutical industry are searching for small-molecule scaffolds for the design of LSD1 inhibitors, mainly because molecules of this type have the potential to be orally active and have better pharmacokinetic properties. Most of the available inhibitors are based on the tranylcypromine scaffold, and thus there is a potential for off-target effects mediated by monoamine oxidase and other flavin-dependent amine oxidases. Triazoles C1 and C15 do not contain a tranylcypromine-like core, and do not inhibit monoamine oxidase. Through the discovery of these triazoles, as well as other small molecule scaffolds, our group is among the leaders in the discovery of small-molecule inhibitors of LSD1.


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

Advantages:  Increased specificity for LSD1, which could reduce off-target effects, and improved pharmacokinetic parameters.

Key Words: 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 Application filed 07/29/2016; EP Application filed 08/01/2016

MUSC-FRD Technology ID: P1412



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