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Towards the Development of an In vivo Chemical Probe for Cyclin G Associated Kinase (GAK).

ABSTRACT: SGC-GAK-1 (1) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, 1 was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of 1 that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-N-(1H-indazol-6-yl)quinolin-4-amine (35) (IC50 = 1.4 ?M), showing improved stability in liver microsomes while still maintaining a narrow spectrum activity across the kinome. As an alternative to scaffold modifications we also explored the use of the broad-spectrum cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) to decrease intrinsic clearance of aminoquinoline GAK inhibitors. Taken together, these approaches point towards the development of an in vivo chemical probe for the dark kinase GAK.

SUBMITTER: Asquith CRM 

PROVIDER: S-EPMC6891286 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Towards the Development of an In vivo Chemical Probe for Cyclin G Associated Kinase (GAK).

Asquith Christopher R M CRM   Bennett James M JM   Su Lianyong L   Laitinen Tuomo T   Elkins Jonathan M JM   Pickett Julie E JE   Wells Carrow I CI   Li Zengbiao Z   Willson Timothy M TM   Zuercher William J WJ  

Molecules (Basel, Switzerland) 20191106 22

SGC-GAK-1 (<b>1</b>) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, <b>1</b> was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of <b>1</b> that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-  ...[more]

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