Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1
| Autor: | Allan E. Rettie, Constanze Wiek, John P. Kowalski, Helmut Hanenberg, Robert D. Pelletier, Matthew G. McDonald |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Metabolite
Medizin Isozyme chemistry.chemical_compound Cell Line Tumor Drug Discovery Cytochrome P-450 Enzyme Inhibitors Humans Cytochrome P450 Family 4 IC50 chemistry.chemical_classification Arachidonic Acid biology Fatty Acids Cytochrome P450 Fatty acid Triazoles Enzyme chemistry Biochemistry Drug Design biology.protein Microsomes Liver Molecular Medicine Arachidonic acid Pharmacophore Oxidation-Reduction |
| Popis: | Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a KI = 2.2 μM and a kinact = 0.15 min-1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer. |
| Databáze: | OpenAIRE |
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