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Identification and optimization of 4-anilinoquinolines as inhibitors of cyclin G associated kinase

Identification and optimization of 4-anilinoquinolines as inhibitors of cyclin G associated kinase
Identification and optimization of 4-anilinoquinolines as inhibitors of cyclin G associated kinase
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.
anilinoquinolines, antibacterial agents, chemical probes, cyclin G associated kinase (GAK)
1860-7179
1-20
Asquith, Christopher R.M.
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Laitinen, Tuomo
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Bennett, James M.
296a6be7-1eb3-4bc1-b89c-83668a2996e5
Godoi, Paulo H.
231e62e3-b531-4697-999b-bf9734a7e614
East, Michael P.
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Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Graves, Lee M.
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Johnson, Gary L.
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Dornsife, Ronna E.
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Wells, Carrow I.
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Elkins, Jonathan M.
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Wilson, Timothy M.
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Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
Asquith, Christopher R.M.
0b3a8a42-97dc-415f-9ab2-45f56547625e
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Bennett, James M.
296a6be7-1eb3-4bc1-b89c-83668a2996e5
Godoi, Paulo H.
231e62e3-b531-4697-999b-bf9734a7e614
East, Michael P.
a2d70b5b-b763-4866-9557-a0f91babb608
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Graves, Lee M.
fd4996e9-fd92-4280-a590-dd9cb13b0ff6
Johnson, Gary L.
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Dornsife, Ronna E.
e6bd038b-0322-4e14-a26e-066a7a8bb9f6
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Elkins, Jonathan M.
103a8855-1ca0-4abb-9ce2-a7c4f350fe39
Wilson, Timothy M.
2935e59e-8856-488b-a1b3-266361256661
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040

Asquith, Christopher R.M., Laitinen, Tuomo, Bennett, James M., Godoi, Paulo H., East, Michael P., Tizzard, Graham J., Graves, Lee M., Johnson, Gary L., Dornsife, Ronna E., Wells, Carrow I., Elkins, Jonathan M., Wilson, Timothy M. and Zuercher, William J. (2017) Identification and optimization of 4-anilinoquinolines as inhibitors of cyclin G associated kinase. ChemMedChem, 2017 (12), 1-20. (doi:10.1002/cmdc.201700663).

Record type: Article

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.

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Accepted/In Press date: 26 October 2017
e-pub ahead of print date: 27 November 2017
Keywords: anilinoquinolines, antibacterial agents, chemical probes, cyclin G associated kinase (GAK)

Identifiers

Local EPrints ID: 416465
URI: https://eprints.soton.ac.uk/id/eprint/416465
ISSN: 1860-7179
PURE UUID: 41f76288-1a54-4921-9827-fb0249a7bc86
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

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Date deposited: 19 Dec 2017 17:30
Last modified: 17 Sep 2019 04:31

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Contributors

Author: Christopher R.M. Asquith
Author: Tuomo Laitinen
Author: James M. Bennett
Author: Paulo H. Godoi
Author: Michael P. East
Author: Lee M. Graves
Author: Gary L. Johnson
Author: Ronna E. Dornsife
Author: Carrow I. Wells
Author: Jonathan M. Elkins
Author: Timothy M. Wilson
Author: William J. Zuercher

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