title: In vitro metabolism of a novel JNK inhibitor tanzisertib: interspecies differences in oxido-reduction and characterization of enzymes involved in metabolism.
abstract: 1. In vitro metabolism of Tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, selective c-Jun amino-terminal kinase (JNK) inhibitor, was investigated in mouse, rat, rabbit, dog, monkey and human hepatocytes over 4 h. The extent of metabolism of [(14)C]tanzisertib was variable, with <10% metabolized in dog and human, <20% metabolized in rabbit and monkey and >75% metabolized in rat and mouse. Primary metabolic pathways in human and dog hepatocytes, were direct glucuronidation and oxidation of cyclohexanol to a keto metabolite, which was subsequently reduced to parent or cis-isomer, followed by glucuronidation. Rat and mouse produced oxidative metabolites and cis-isomer, including direct glucuronides and sulfates of tanzisertib and cis-isomer. 2. Enzymology of oxido-reductive pathways revealed that human aldo-keto reductases AKR1C1, 1C2, 1C3 and 1C4 were responsible for oxido-reduction of tanzisertib, CC-418424 and keto tanzisertib. Characterizations of enzyme kinetics revealed that AKR1C4 had a high affinity for reduction of keto tanzisertib to tanzisertib compared to other isoforms. These results demonstrate unique stereoselectivity of the reductive properties documented by human AKR1C enzymes for the same substrate. 3. Characterization of UGT isoenzymes in glucuronidation of tanzisertib and CC-418424 revealed that, tanzisertib glucuronide was catalyzed by: UGT1A1, 1A4, 1A10 and 2B4, while CC-418424 glucuronidation was catalyzed by UGT2B4 and 2B7.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Celgene Corporation , Summit, NJ , USA and.
authors.forename: Christian
authors.initials: C
authors.lastname: Atsriku
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Mehran
authors.initials: M
authors.lastname: Moghaddam
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D000818:Animals; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047428:Protein Kinase Inhibitors; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C000614209:AKR7A5 protein, mouse; D014453:Glucuronosyltransferase; D048670:MAP Kinase Kinase 4
keywords: Aldo-keto reductase; C-Jun amino-terminal kinase; cis–trans isomerization; enzyme phenotyping; stereoselectivity; tanzisertib