Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton’s Tyrosine Kinase

The
discovery and optimization of a series of 4-aminocinnoline-3-carboxamide
inhibitors of Bruton’s tyrosine kinase are reported. A fragment-based
screening approach incorporating X-ray co-crystallography was used
to identify a cinnoline fragment and characterize its binding mode
in the ATP binding site of Btk. Optimization of the fragment hit resulted
in the identification of a lead compound which reduced paw swelling
in a dose- and exposure-dependent fashion in a rat model of collagen-induced
arthritis.