Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition
Autor: | Christopher R. M. Asquith, William J. Zuercher, Julie E. Pickett, Timothy M. Willson, James M. Bennett, Carrow I. Wells, Zengbiao Li, Lianyong Su, Jonathan M. Elkins, Tuomo Laitinen |
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Rok vydání: | 2019 |
Předmět: |
0303 health sciences
genetic structures biology Chemistry Kinase Cytochrome P450 Chemical probe Pharmacology behavioral disciplines and activities 030226 pharmacology & pharmacy 3. Good health 03 medical and health sciences 0302 clinical medicine Orally active nervous system Plasma exposure In vivo biology.protein Liver microsomes psychological phenomena and processes 030304 developmental biology Cyclin |
DOI: | 10.1101/629220 |
Popis: | SGC-GAK-1 (1), a potent, selective, cell-active chemical probe for cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limiting its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also greatly improved plasma exposure of 1 in mice, supporting its use as a chemical probe to study the in vivo biology of GAK inhibition. |
Databáze: | OpenAIRE |
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