1. Academic Validation
  2. Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1

Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1

  • J Med Chem. 2020 May 14;63(9):4824-4836. doi: 10.1021/acs.jmedchem.0c00101.
John P Kowalski 1 Matthew G McDonald 1 Robert D Pelletier 1 Helmut Hanenberg 2 Constanze Wiek 3 Allan E Rettie 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98105, United States.
  • 2 Department of Pediatrics III, University Children's Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
  • 3 Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich-Heine University, 40225 Düsseldorf, Germany.
Abstract

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.

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