PT  - JOURNAL ARTICLE
AU  - Christopher R. M. Asquith
AU  - James M. Bennett
AU  - Lianyong Su
AU  - Tuomo Laitinen
AU  - Jonathan M. Elkins
AU  - Julie E. Pickett
AU  - Carrow I. Wells
AU  - Zengbiao Li
AU  - Timothy M. Willson
AU  - William J. Zuercher
TI  - Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition
AID  - 10.1101/629220
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 629220
4099  - http://biorxiv.org/content/early/2019/05/07/629220.short
4100  - http://biorxiv.org/content/early/2019/05/07/629220.full
AB  - 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.