Identifying simultaneous matrix metalloproteinases/soluble epoxide hydrolase inhibitors

• Published in: Molecular and cellular biochemistry 2022-03, Vol.477 (3), p.877-884
• Main Authors: El-Sherbeni, Ahmed A., Bhatti, Rabia, Isse, Fadumo A., El-Kadi, Ayman O. S.
• Format: Article
• Language: English
• Subjects: Acids; Biochemistry; Biological effects; Biomedical and Life Sciences; Cardiology; Cardiomyocytes; Cardiovascular diseases; Chromatography; Enzymes; Epoxide hydrolase; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - chemistry; Extracellular matrix; Humans; Hydrolases; Inhibitors; Life Sciences; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Matrix metalloproteinase; Matrix Metalloproteinase 2 - chemistry; Matrix Metalloproteinase Inhibitors - chemistry; Matrix metalloproteinases; Medical Biochemistry; Metalloproteinase; Metastasis; Oncology; Pharmacy; Scientific imaging; Spectrophotometry; Staphylococcal enterotoxin H; Substrates
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-021-04337-5

Matrix metalloproteinase (MMP) and soluble epoxide hydrolase (sEH) have completely unrelated biological functions; however, their dysregulation produce similar effects on biological systems. Based on the similarity in the reported structural requirements for their inhibition, the current study aimed to identify a simultaneous inhibitor for MMP and sEH. Six compounds were identified as potential simultaneous MMP/sEH inhibitors and tested for their capacity to inhibit MMP and sEH. Inhibition of MMP and sEH activity using their endogenous and exogenous substrates was measured by liquid chromatography/mass spectrometry, spectrophotometry, and zymography. Two compounds, CTK8G1143 and ONO-4817, were identified to inhibit both MMP and sEH activity. CTK8G1143 and ONO-4817 inhibited the recombinant human sEH activity by an average of 67.4% and 55.2%, respectively. The IC 50 values for CTK8G1143 and ONO-4817 to inhibit recombinant human sEH were 5.2 and 3.5 µM, respectively, whereas their maximal inhibition values were 71.4% and 42.8%, respectively. Also, MMP and sEH activity of human cardiomyocytes were simultaneously inhibited by CTK8G1143 and ONO-4817. Regarding other compounds, they showed either MMP or sEH inhibitory activity but not both. In conclusion, these two simultaneous inhibitors of MMP and sEH could provide a promising intervention for the prevention and control of several diseases, especially cardiovascular diseases.