Synthesis of fused isothiazole derivatives as inhibitors of cyclin G associated kinase (GAK) and phosphoinositide kinase FYVE-type zinc finger (PIKfyve)

Previous research in our lab led to the discovery of 6-aryl-isothiazolo[4,3-b]pyridines as potent and selective inhibitors of either cyclin G associated kinase (GAK) or phosphoinositide kinase FYVE-type zinc finger (PIKfyve). Both kinases are promising drug targets for the development of broadspectrum antiviral agents. Using the current chemistry, 3,6-disubstituted isothiazolo[4,3-b]pyridines can easily be prepared. In this project proposal, we will focus on the establishment of synthetic procedures to have access to novel fused isothiazolo derivatives, which will allow us to broaden chemical space that can be studied as GAK and PIKfyve inhibitors. The design will be guided by molecular modeling and biochemical kinase assays. Promising compounds will be investigated for activity against various viruses, such as the dengue virus and the venezuelan equine encephalitis virus.