Towards the development of an in vivo chemical probe for cyclin G associated kinase (GAK)

Journal article

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 μM), 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.

Authors: Asquith, C; Bennett, J; Su, L; Laitinen, T; Elkins, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Molecules
• Volume: 24
• Issue: 22
• Article number: 4016
• Publication date: 2019-11-06
• Acceptance date: 2019-11-02
• DOI: 10.3390/molecules24224016
• ISSN: 1420-3049
• Pmid: 31698822
• Language: English
• Keywords: FFR