2. Academic Validation
  3. Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents

Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents

  • J Med Chem. 2015 Apr 23;58(8):3393-410. doi: 10.1021/jm501759m.
Sona Kovackova 1 2,  Lei Chang 1 2,  Elena Bekerman 3,  Gregory Neveu 3,  Rina Barouch-Bentov 3,  Apirat Chaikuad 4,  Christina Heroven 4,  Michal Šála 1 2,  Steven De Jonghe 1 2,  Stefan Knapp 4,  Shirit Einav 3,  Piet Herdewijn 1 2
Affiliations

Affiliations

  • 1 †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
  • 2 ‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
  • 3 §Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 4 ∥Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
PMID: 25822739 DOI: 10.1021/jm501759m
Abstract

Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral Infection, Cancer, and Parkinson's disease).

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