title: Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase.
abstract: Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of nonazole CYP26A1 selective inhibitors was identified with low nM potency. The lead compound 3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl] phenyl}4-propanoic acid (24) had 43-fold selectivity toward CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogues also inhibited atRA metabolism in HepG2 cells, resulting in increased potency of atRA toward RAR activation. The identified compounds have potential to become novel treatments aiming to elevate endogenous atRA concentrations and may be useful as cotreatment with atRA to combat therapy resistance.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, The University of Montana , 32 Campus Drive, Missoula, Montana 59812, United States.|DermaXon LLC , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Philippe
authors.initials: P
authors.lastname: Diaz
authors.affiliation: Department of Pharmaceutics, University of Washington , 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
authors.forename: Weize
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, The University of Montana , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Keyari
authors.affiliation: Department of Pharmaceutics, University of Washington , 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Buttrick
authors.affiliation: Department of Pharmaceutics, University of Washington , 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Price
authors.affiliation: DermaXon LLC , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilloteau
authors.affiliation: Department of Pharmaceutics, University of Washington , 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, The University of Montana , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Vanessa G
authors.initials: VG
authors.lastname: Sperandio
authors.affiliation: Chemistry Department, Louisiana State University , 232 Choppin Hall, Baton Rouge, Louisiana 70803, United States.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.affiliation: DermaXon LLC , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Fanny
authors.initials: F
authors.lastname: Astruc-Diaz
authors.affiliation: Department of Pharmaceutics, University of Washington , 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
mesh_terms: D000465:Algorithms; D000818:Animals; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D015195:Drug Design; D004351:Drug Resistance; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D000072516:Retinoic Acid 4-Hydroxylase; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014212:Tretinoin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; C000607082:Cyp26b1 protein, rat; D000072516:Retinoic Acid 4-Hydroxylase