2. Academic Validation
  3. LKY-047: First Selective Inhibitor of Cytochrome P450 2J2

LKY-047: First Selective Inhibitor of Cytochrome P450 2J2

  • Drug Metab Dispos. 2017 Jul;45(7):765-769. doi: 10.1124/dmd.117.075036.
Nguyen Minh Phuc 1,  Zhexue Wu 1,  Yuseok O 1,  Jee-Hyun Lee 1,  Sangtaek Oh 1,  Gyu-Yong Song 2,  Kwang-Hyeon Liu 2
Affiliations

Affiliations

  • 1 BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Department of Bio and Fermentation Convergence Technology, BK21 PLUS Program, Kookmin University, Seoul, Korea (S.O.).
  • 2 BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Department of Bio and Fermentation Convergence Technology, BK21 PLUS Program, Kookmin University, Seoul, Korea (S.O.) [email protected] [email protected].
PMID: 28461575 DOI: 10.1124/dmd.117.075036
Abstract

Highly selective Cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other Cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole O-demethylase and terfenadine hydroxylase activity, with Ki values of 0.96 and 2.61 μM, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a Ki value of 3.61 μM. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC50 > 50 μM). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays.

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