Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton’s Tyrosine Kinase
Copyright policy )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.
- Takeda (Japan) Japan
Male, Models, Molecular, Binding Sites, Protein Conformation, Arthritis, Protein-Tyrosine Kinases, Ligands, Rats, Small Molecule Libraries, Mice, Adenosine Triphosphate, Dogs, Drug Discovery, Agammaglobulinaemia Tyrosine Kinase, Animals, Female, Collagen, Protein Kinase Inhibitors
Male, Models, Molecular, Binding Sites, Protein Conformation, Arthritis, Protein-Tyrosine Kinases, Ligands, Rats, Small Molecule Libraries, Mice, Adenosine Triphosphate, Dogs, Drug Discovery, Agammaglobulinaemia Tyrosine Kinase, Animals, Female, Collagen, Protein Kinase Inhibitors
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