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

  • ChemMedChem. 2018 Jan 8;13(1):48-66. doi: 10.1002/cmdc.201700663.
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
  • 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.
PMID: 29072804 DOI: 10.1002/cmdc.201700663
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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