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

We recently reported the discovery of isothiazolo4,3-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 isothiazolo4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with K_d values in the low micromolar range that can serve as chemical starting points for the discovery of GAK inhibitors based on a different scaffold.