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

Christopher R M Asquith,Timothy M Willson,Lianyong Su,Carrow I Wells,James M Bennett,Jonathan M Elkins,William J Zuercher,Julie E Pickett,Tuomo Laitinen,Zengbiao Li

doi:10.3390/molecules24224016

Christopher R M Asquith, Timothy M Willson + Show 8 more

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https://doi.org/10.3390/molecules24224016

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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 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.

Highlights

IntroductionCyclin G-associated kinase (GAK) is a 160 kDa member of the numb-associated kinase (NAK)
Cyclin G-associated kinase (GAK) is a 160 kDa member of the numb-associated kinase (NAK)family of serine/threonine kinases [1]
We describe our efforts in the optimization of 4-aminoquinolines as potential in vivo chemical probes for GAK

Summary

Introduction

Cyclin G-associated kinase (GAK) is a 160 kDa member of the numb-associated kinase (NAK). Family of serine/threonine kinases [1]. GAK was originally identified as a directly associated partner of cyclin G, and is ubiquitously expressed across tissues [2]. Cytoplasm, and nucleus [3]. GAK has been genetically associated with a diverse range of biological processes. Genome-wide association studies have identified single nucleotide. Molecules 2019, 24, 4016 of biological processes. Genome-wide association studies have identified single nucleotide polymorphisms thatare areassociated associated with susceptibility to Parkinson’s [4].down

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