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ChemMedChem. 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.

Author information

1
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
2
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
3
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
4
Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, 13083-886, Brazil.
5
Department of Pharmacology, University of North Carolina at Chapel Hill, NC, 27599, USA.
6
UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.

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)

PMID:
29072804
PMCID:
PMC5914168
[Available on 2019-01-08]
DOI:
10.1002/cmdc.201700663
[Indexed for MEDLINE]

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