Cyclin G-associated kinase (GAK) affinity and antiviral activity studies of a series of 3-C-substituted isothiazolo[4,3-b]pyridines.
Antiviral drugs
Cyclin G-associated kinase
Dengue virus
Kinase inhibitor
isothiazolo[4,3-b]pyridine
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Feb 2019
01 Feb 2019
Historique:
received:
10
10
2018
revised:
21
11
2018
accepted:
27
11
2018
pubmed:
12
12
2018
medline:
12
2
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
Cyclin G-associated kinase (GAK) is a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which regulates intracellular trafficking of dengue virus during early and late stages of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promising antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4,3-b]pyridines with a carbon-linked substituent at position 3 is described by the application of regioselective Suzuki and Sonogashira coupling reactions. A derivative with a 3,4-dimethoxyphenyl residue at position 3 demonstrates low nanomolar binding affinity for GAK and antiviral activity against dengue virus. These findings reveal that appropriate substitution of a phenyl moiety at position 3 of the scaffold can improve GAK binding affinity.
Identifiants
pubmed: 30529544
pii: S0223-5234(18)31024-9
doi: 10.1016/j.ejmech.2018.11.065
pii:
doi:
Substances chimiques
Antiviral Agents
0
Cyclin G
0
Intracellular Signaling Peptides and Proteins
0
Pyridines
0
Thiazoles
0
isothiazolo(5,4-b)pyridine
0
GAK protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Cyclic GMP-Dependent Protein Kinases
EC 2.7.11.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
256-265Informations de copyright
Copyright © 2018 Elsevier Masson SAS. All rights reserved.