Cyclin G-associated kinase (GAK) affinity and antiviral activity studies of a series of 3-C-substituted isothiazolo[4,3-b]pyridines.

Affiliation

Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, bus 1041, 3000, Leuven, Belgium. Electronic address: [Email]

Abstract

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.

Keywords

Antiviral drugs,Cyclin G-associated kinase,Dengue virus,Kinase inhibitor,isothiazolo[4,3-b]pyridine,