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

Sona Kovackova; Lei Chang; Elena Bekerman; Gregory Neveu; Rina Barouch-Bentov; Apirat Chaikuad; Christina Heroven; Michal Šála; Steven De Jonghe; Stefan Knapp; Shirit Einav; Piet Herdewijn

doi:10.1021/jm501759m

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. Epub 2015 Apr 9.

Authors

Sona Kovackova^{1

2}, Lei Chang^{1

2}, Elena Bekerman³, Gregory Neveu³, Rina Barouch-Bentov³, Apirat Chaikuad⁴, Christina Heroven⁴, Michal Šála^{1

2}, Steven De Jonghe^{1

2}, Stefan Knapp⁴, Shirit Einav³, Piet Herdewijn^{1

2}

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.

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry*
Antiviral Agents / pharmacology*
Cell Line
Crystallography, X-Ray
Hepacivirus / drug effects*
Hepacivirus / physiology
Hepatitis C / drug therapy*
Hepatitis C / enzymology
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / chemistry
Intracellular Signaling Peptides and Proteins / metabolism
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Pyridines / chemistry*
Pyridines / pharmacology*
Thiazoles / chemistry*
Thiazoles / pharmacology*
Virus Internalization / drug effects

Substances

Antiviral Agents
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyridines
Thiazoles
isothiazolo(5,4-b)pyridine
GAK protein, human
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding