Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ζ Inhibitors with Fragment-Merging Strategy.

Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information.