Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition

Abstract

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.