A Scaffold-Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase.

We recently reported the discovery of isothiazolo[4,3-b]pyridine-based inhibitors of cyclin G associated kinase (GAK) displaying low nanomolar binding affinity for GAK and demonstrating broad-spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold-hopping approach was applied starting from two different isothiazolo[4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar range that can serve as chemical starting points for the discovery of GAK inhibitors based on a different scaffold.