RT Journal Article
SR Electronic
T1 Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 629220
DO 10.1101/629220
A1 Christopher R. M. Asquith
A1 James M. Bennett
A1 Lianyong Su
A1 Tuomo Laitinen
A1 Jonathan M. Elkins
A1 Julie E. Pickett
A1 Carrow I. Wells
A1 Zengbiao Li
A1 Timothy M. Willson
A1 William J. Zuercher
YR 2019
UL http://biorxiv.org/content/early/2019/05/07/629220.abstract
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.