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. Furthermore, our optimization
effort identified the highly potent and orally available 5,7-isoquinoline 37 from the second chemical series. Compound 37 showed good efficacy in a mouse collagen-induced arthritis model.
The in vivo studies suggest that PKCζ inhibition is a novel
target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biological consequences
of PKCζ inhibition, specifically in terms of therapeutic intervention
for RA.