Identification and Characterization of Novel Small-Molecule SMOX Inhibitors
The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxi...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Medical Sciences |
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| Online Access: | https://www.mdpi.com/2076-3271/10/3/47 |
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| author | Amelia B. Furbish Ahmed S. Alford Pieter Burger Yuri K. Peterson Tracy Murray-Stewart Robert A. Casero Patrick M. Woster |
| author_facet | Amelia B. Furbish Ahmed S. Alford Pieter Burger Yuri K. Peterson Tracy Murray-Stewart Robert A. Casero Patrick M. Woster |
| author_sort | Amelia B. Furbish |
| collection | DOAJ |
| description | The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H<sub>2</sub>O<sub>2</sub> and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors <b>6</b> (IC<sub>50</sub> 0.54 μM, Ki 1.60 μM) and <b>7</b> (IC<sub>50</sub> 0.23 μM, K<sub>i</sub> 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury. |
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| institution | Directory Open Access Journal |
| issn | 2076-3271 |
| language | English |
| last_indexed | 2024-03-09T23:12:57Z |
| publishDate | 2022-08-01 |
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| series | Medical Sciences |
| spelling | doaj.art-a8cb1942ba104f0a89106e36a78159a62023-11-23T17:41:48ZengMDPI AGMedical Sciences2076-32712022-08-011034710.3390/medsci10030047Identification and Characterization of Novel Small-Molecule SMOX InhibitorsAmelia B. Furbish0Ahmed S. Alford1Pieter Burger2Yuri K. Peterson3Tracy Murray-Stewart4Robert A. Casero5Patrick M. Woster6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USADepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USADepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USADepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USASidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins School of Medicine, 1650 Orleans St. Room 551, Baltimore, MD 21287, USASidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins School of Medicine, 1650 Orleans St. Room 551, Baltimore, MD 21287, USADepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USAThe major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H<sub>2</sub>O<sub>2</sub> and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors <b>6</b> (IC<sub>50</sub> 0.54 μM, Ki 1.60 μM) and <b>7</b> (IC<sub>50</sub> 0.23 μM, K<sub>i</sub> 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury.https://www.mdpi.com/2076-3271/10/3/47spermine oxidasepolyaminesoxidative stressacroleinexcitotoxicitypolyamine oxidase |
| spellingShingle | Amelia B. Furbish Ahmed S. Alford Pieter Burger Yuri K. Peterson Tracy Murray-Stewart Robert A. Casero Patrick M. Woster Identification and Characterization of Novel Small-Molecule SMOX Inhibitors Medical Sciences spermine oxidase polyamines oxidative stress acrolein excitotoxicity polyamine oxidase |
| title | Identification and Characterization of Novel Small-Molecule SMOX Inhibitors |
| title_full | Identification and Characterization of Novel Small-Molecule SMOX Inhibitors |
| title_fullStr | Identification and Characterization of Novel Small-Molecule SMOX Inhibitors |
| title_full_unstemmed | Identification and Characterization of Novel Small-Molecule SMOX Inhibitors |
| title_short | Identification and Characterization of Novel Small-Molecule SMOX Inhibitors |
| title_sort | identification and characterization of novel small molecule smox inhibitors |
| topic | spermine oxidase polyamines oxidative stress acrolein excitotoxicity polyamine oxidase |
| url | https://www.mdpi.com/2076-3271/10/3/47 |
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