Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Cyclin G-associated kinase, Kinase inhibitor, Isothiazolo[4,3-b]pyridine, Dengue virus, Antiviral agents, Antiviral Agents, Cell Line, Tumor, Cell Survival, Dengue Virus, Dose-Response Relationship, Drug, Drug Discovery, Humans, Intracellular Signaling Peptides and Proteins, Microbial Sensitivity Tests, Molecular Structure, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Structure-Activity Relationship, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety generated potent GAK inhibitors with IC50 values in a low nanomolar range. This potent GAK binding affinity was rationalized by molecular modelling demonstrating that the carboxamide moiety engages in an extra hydrogen bond with GAK. Moreover, this new series of compounds was also endowed with antiviral activity against dengue virus, highlighting the potential utility of GAK as a target for the development of antiviral drugs.