LSD1 Protein Inhibitors as Cancer Therapeutics


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. 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, 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. These compounds are also selective for LSD1 over monoamine oxidase MAO A and B. Preliminary studies have shown that two of the compounds inhibit LSD1 (IC50 228.3 and 192.4 nM) without inhibiting MAO and promote increases in histone lysine methylation at histone 3 lysine 4 (H3K4). In addition, a subset of 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) in vitro. SMOX is a key component of the polyamine back-conversion pathway and has recently been implicated as a causative factor in gastric cancers. One identified compound, 59, inhibited SMOX with an IC50 of 25.71 μM. This compound is significantly more potent than the known polyamine oxidase inhibitor MDL 72527 (IC50 = 89.7 μM) and retains good activity against LSD1.

Further, to demonstrate the potential for these molecules as cancer therapeutics, researchers tested pancreatic cell lines Miapaca-2 and BxPC-3. In the Miapaca-2 cell line, it was found that compound 5 had similar IC50 values as the current used therapy for pancreatic cancer, gemcitabine, while the most potent SMOX inhibitor, 59, had a significantly higher IC50 value. In the BxPC-3 cell line, Gemcitabine inhibits cell growth with an IC50 value of 5.71 uM and plateaus at 30% inhibition, while the most potent SMOX inhibitor 59, has an IC50 of 61.5 uM. These data suggest that cytotoxicity of these 3,5-diamino-1,2,4-triazoles in the MiaPaCa2 cell line may be mediated by an as yet unknown mechanism and may correspond with the expression level of SMOX in the BxPc-3 cell line.


Overview: LSD1 is a histone demethlyase that catalyzes the oxidative demethylation of specific histone lysines, 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 specific LSD1 inhibitors. Most of the available inhibitors are based on the tranylcypromine scaffold, and thus there is a potential for off-target effects mediated by MAO which can produce undesirable side effects, 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: Holshouser, Steven, et al. “Dual inhibitors of LSD1 and spermine oxidase” MedChemComm (2019); 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: P1412




Patent Information:
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Docket BioPharma
Zucker Institute of Innovation Commercialization powered by MUSC
Patrick Woster
Craig Kutz
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