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. 2018 Jan 8;13(1):48-66.
doi: 10.1002/cmdc.201700663. Epub 2017 Nov 27.

Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase

Christopher R M Asquith  1 , Tuomo Laitinen  2 , James M Bennett  3 , Paulo H Godoi  4 , Michael P East  5 , Graham J Tizzard  6 , Lee M Graves  5 , Gary L Johnson  5 , Ronna E Dornsife  1 , Carrow I Wells  1 , Jonathan M Elkins  3   4 , Timothy M Willson  1 , William J Zuercher  1
Affiliations

Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase

Christopher R M Asquith et al. ChemMedChem. .

Abstract

4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.

Keywords: anilinoquinolines; antibacterial agents; chemical probes; cyclin G associated kinase (GAK).

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Figures

Figure 1
Figure 1
Known compounds with reported GAK activity
Figure 2
Figure 2
PKIS/PKIS2 quinoline and quinazoline hit compounds and GAK activities
Figure 3
Figure 3
Active site WaterMap of compounds in GAK: A - Visualised GAK active site interaction of 49, B - WaterMap of 49, C - WaterMap of 1, D/E - WaterMap of 5 favoured (D) and unfavoured (E), F - WaterMap of 9
Figure 4
Figure 4
Correlation of GAK DSF ∆Tm vs-Log GAK Ki
Figure 5
Figure 5
A - Compound 1 is highly selective for GAK. SUM159 cell lysates were incubated with DMSO or the indicated concentration of 1 for 30 minutes on ice. Kinases were then affinity purified using multiplexed inhibitor beads (MIBs) and analyzed by mass spectrometry. Kinase abundance was quantified label free using MaxQuant software. Bars represent the ratio of label free quantification values for the indicated kinase in lysate treated with drug over DMSO control lysates. A dose dependent decrease in kinase ratio indicates 1 binding. B - Compound 49 is highly selective for GAK, under the same conditions as 1. C - GAK and RIPK2 enrichment from experiment with 1. D - GAK and RIPK2 enrichment from experiment with 49.
Figure 6
Figure 6
Comparison of GAK binding of compound 1 (A) and 13 (B). The quinoline scaffold is a tighter binder then the quinazoline despite the possibility for an additional hinge binding interaction.
Scheme 1
Scheme 1
Preparation of quinoline and quinazoline based GAK inhibitors
See this image and copyright information in PMC

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