Evidence map›Paper›PMID 25845827›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2015

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, Jason S Halladay

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
9.2field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed, 61 citations in OpenAlex.

  1. Trial
  2. Article
  3. Review
  4. Enzyme Kinetics, Pharmacokinetics, and Inhibition of Aldehyde Oxidase.Methods in molecular biology (Clifton, N.J.) · 2021
    Article
  5. Review
  6. Article
  7. Review
  8. Article
  9. Article
  10. Article
  11. Fast Methods for Prediction of Aldehyde Oxidase-Mediated Site-of-Metabolism.Computational and structural biotechnology journal · 2019
    Article
  12. Article
  13. Structure-metabolism relationships inProceedings of the National Academy of Sciences of the United States of America · 2017
    Article
  14. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 1 institution in 1 country.

Jasleen K SodhiDepartments 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.com.
Susan WongDepartments 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 KirkpatrickDepartments 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 LiuDepartments 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 KhojastehDepartments 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 HopDepartments 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 BarrDepartments 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 JonesDepartments 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 HalladayDepartments 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.).
Washington State University · US

Funding

Understanding the Metabolic Impact of Aldehyde Oxidase on New Drug DesignR01GM100874 · NIGMS · WASHINGTON STATE UNIVERSITY · PI JONES, JEFFREY P · 2012 to 2019
$2.6M
NIGMS NIH HHS GM100874NIGMS NIH HHS R01 GM100874
6 · The paper itself

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.

Indexed as

Models, MolecularAgammaglobulinaemia Tyrosine KinaseAldehyde OxidaseAnimalsAnti-Inflammatory Agents, Non-SteroidalBiocatalysisCatalytic DomainCytosolDrugs, InvestigationalDrug StabilityGene Expression ProfilingHumansHydrolysisKineticsLiverMolecular ConformationAgammaglobulinaemia Tyrosine KinaseAldehyde OxidaseAnti-Inflammatory Agents, Non-SteroidalAOX1 protein, humanDrugs, InvestigationalN-(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-carboxamideProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinonesThiophenes

Identifiers

PMID25845827
PMCPMC4429680
OpenAlexW2156044670

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.