Journal article
A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834
Drug metabolism and disposition, Vol.43(6), pp.908-915
06/2015
Handle:
https://hdl.handle.net/2376/101366
PMCID: PMC4429680
PMID: 25845827
Abstract
GDC-0834, a Bruton's tyrosine kinase inhibitor investigated as a potential treatment of rheumatoid arthritis, was previously reported to be extensively metabolized by amide hydrolysis such that no measurable levels of this compound were detected in human circulation after oral administration. In vitro studies in human liver cytosol determined that GDC-0834 (R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxamide) was rapidly hydrolyzed with a CLint of 0.511 ml/min per milligram of protein. Aldehyde oxidase (AO) and carboxylesterase (CES) were putatively identified as the enzymes responsible after cytosolic fractionation and mass spectrometry-proteomics analysis of the enzymatically active fractions. Results were confirmed by a series of kinetic experiments with inhibitors of AO, CES, and xanthine oxidase (XO), which implicated AO and CES, but not XO, as mediating GDC-0834 amide hydrolysis. Further supporting the interaction between GDC-0834 and AO, GDC-0834 was shown to be a potent reversible inhibitor of six known AO substrates with IC50 values ranging from 0.86 to 1.87 μM. Additionally, in silico modeling studies suggest that GDC-0834 is capable of binding in the active site of AO with the amide bond of GDC-0834 near the molybdenum cofactor (MoCo), orientated in such a way to enable potential nucleophilic attack on the carbonyl of the amide bond by the hydroxyl of MoCo. Together, the in vitro and in silico results suggest the involvement of AO in the amide hydrolysis of GDC-0834.
Metrics
9 Record Views
Details
- Title
- A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834
- Creators
- Jasleen K Sodhi - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.) jasleens@gene.comSusan Wong - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)Donald S Kirkpatrick - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)Lichuan Liu - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)S Cyrus Khojasteh - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)Cornelis E C A Hop - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)John T Barr - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)Jeffrey P Jones - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)Jason S Halladay - Departments of Drug Metabolism and Pharmacokinetics (J.K.S., S.W., S.C.K., C.E.C.A.H., J.S.H.), Clinical Pharmacology (L.L.), and Protein Chemistry (D.S.K.), Genentech, Inc., South San Francisco, California; and Department of Chemistry, Washington State University, Pullman, Washington (J.T.B., J.P.J.)
- Publication Details
- Drug metabolism and disposition, Vol.43(6), pp.908-915
- Academic Unit
- Chemistry, Department of
- Publisher
- United States
- Grant note
- R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
- Identifiers
- 99900546534301842
- Language
- English
- Resource Type
- Journal article