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

Asquith, C. R. M.; Bennett, J. M.; Su, L.; Latinen, T.; Elkins, J. M.; Pickett, J. E.; Wells, C. I.; Li, Z.; Willson, T. M.; Zuercher, W. J.

doi:10.1101/629220

bioRxiv · 10.1101/629220

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

Asquith, C. R. M.·Bennett, J. M.·Su, L.·Latinen, T.·Elkins, J. M.·Pickett, J. E.·Wells, C. I.·Li, Z.·Willson, T. M.·Zuercher, W. J.

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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.

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Asquith, C. R. M., Bennett, J. M., Su, L., Latinen, T., Elkins, J. M., Pickett, J. E., Wells, C. I., Li, Z., Willson, T. M., Zuercher, W. J.. 2019-05-07. Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition. https://doi.org/10.1101/629220

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