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Research ArticleArticle

A Novel Reaction Mediated by Human Aldehyde Oxidase: Amide Hydrolysis of GDC-0834

Jasleen K. Sodhi, Susan Wong, Donald S. Kirkpatrick, Lichuan Liu, S. Cyrus Khojasteh, Cornelis E. C. A. Hop, John T. Barr, Jeffrey P. Jones and Jason S. Halladay
Drug Metabolism and Disposition June 2015, 43 (6) 908-915; DOI: https://doi.org/10.1124/dmd.114.061804
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.)
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Susan 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.)
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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.)
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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.)
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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.)
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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.)
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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.)
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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.)
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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.)
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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.

Footnotes

    • Received October 28, 2014.
    • Accepted April 6, 2015.
  • ↵1 Current affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.

  • The in silico modelling work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM100874] (J.P.J., J.T.B.)

  • dx.doi.org/10.1124/dmd.114.061804.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (6)
Drug Metabolism and Disposition
Vol. 43, Issue 6
1 Jun 2015
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Research ArticleArticle

Amide Hydrolysis Mediated by Human Aldehyde Oxidase

Jasleen K. Sodhi, Susan Wong, Donald S. Kirkpatrick, Lichuan Liu, S. Cyrus Khojasteh, Cornelis E. C. A. Hop, John T. Barr, Jeffrey P. Jones and Jason S. Halladay
Drug Metabolism and Disposition June 1, 2015, 43 (6) 908-915; DOI: https://doi.org/10.1124/dmd.114.061804

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Research ArticleArticle

Amide Hydrolysis Mediated by Human Aldehyde Oxidase

Jasleen K. Sodhi, Susan Wong, Donald S. Kirkpatrick, Lichuan Liu, S. Cyrus Khojasteh, Cornelis E. C. A. Hop, John T. Barr, Jeffrey P. Jones and Jason S. Halladay
Drug Metabolism and Disposition June 1, 2015, 43 (6) 908-915; DOI: https://doi.org/10.1124/dmd.114.061804
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