Dual inhibitors of LSD1 and spermine oxidase

Holshouser, Steven; Dunworth, Matthew; Murray-Stewart, Tracy; Peterson, Yuri K.; Burger, Pieter B.; Kirkpatrick, Joy E; Chen, Huan Huan; Casero, Robert A.; Woster, Patrick M.

doi:10.1039/c8md00610e

Cited by 25 publications

(24 citation statements)

References 29 publications

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“…To test if SMOX affects β-catenin activation in a human model system, gastric organoids were generated from human surgical samples as described [ 29 ], cultured as monolayers, and then infected with H. pylori , in the presence or absence of the novel SMOX inhibitor SLH150–54 [ 30 ]. H. pylori infection increased spermidine levels in these human GECS, and SLH150–54 significantly inhibited this response ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling

et al. 2020

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Helicobacter pylori infection is the main risk factor for development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori , and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus H 2 O 2 , is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox -deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori -induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox −/− gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori -infected Smox −/− mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori -induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.

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Section: Resultsmentioning

confidence: 99%

Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling

et al. 2020

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“…The activity of 2,11-Met2-Spm towards SMOX (IC 50 = 169 μM) was worse than that reported for MDL72527 (IC 50 = 90 μM [ 14 ]), which is an irreversible PAOX inhibitor of a Put nature with reactive allene substituents. As a Spm derivative, it is likely that 2,11-Met2-Spm will be less inhibitory of PAOX (natural substrates are N 1-Ac-Spd and less effective N 1-Ac-Spm) compared with SMOX.…”

Section: Resultsmentioning

confidence: 75%

“…SI-4650 inhibited cell growth, induced apoptosis, and promoted autophagy, making it a compound of interest for cancer treatment [ 12 ]. Recently, among a family of N -substituted 3,5-diamino-1,2,4-triazoles, an efficient and specific inhibitor of SMOX, N 5-(2-([1,1′-biphenyl]-4-yloxy) benzyl)-1 H -1,2,4-triazole-3,5-diamine, was identified as having an IC 50 value of 25 μM (the compound had an IC 50 value of >200 μM towards PAOX); this compound efficiently inhibited SMOX in cell culture [ 14 ]. Currently, this is the one compound that is significantly more effective towards SMOX than PAOX.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel substrate-derived spermine oxidase inhibitor

et al. 2020

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Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in M-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 M towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.

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“…Moreover, Holshouser et al. 55 and Kutz et al. 56 also reported a class of compounds containing 3,5-diamino-1,2,4-triazoles as novel inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

Wang

You

et al. 2020

Acta Pharmaceutica Sinica B

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Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC 50 = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

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Dual inhibitors of LSD1 and spermine oxidase

Abstract: Dual inhibitors of LSD1 and SMOX, with no activity against N1-acetylpolyamine oxidase (PAOX).

Cited by 25 publications

References 29 publications

Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling

Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling

Identification of a novel substrate-derived spermine oxidase inhibitor

Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

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