title: Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents.
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).
authors.affiliation: †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.|‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Sona
authors.initials: S
authors.lastname: Kovackova
authors.affiliation: †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.|‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.affiliation: §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.
authors.forename: Elena
authors.initials: E
authors.lastname: Bekerman
authors.affiliation: §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.
authors.forename: Gregory
authors.initials: G
authors.lastname: Neveu
authors.affiliation: §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.
authors.forename: Rina
authors.initials: R
authors.lastname: Barouch-Bentov
authors.affiliation: ∥Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: ∥Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Heroven
authors.affiliation: †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.|‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.|‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.affiliation: ∥Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: §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.
authors.forename: Shirit
authors.initials: S
authors.lastname: Einav
authors.affiliation: †Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.|‡Interface Valorisation Platform, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; C476000:isothiazolo(5,4-b)pyridine; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases
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