title: Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.
abstract: 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.
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Smith
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Mallareddy
authors.initials: M
authors.lastname: Komandla
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Toufike
authors.initials: T
authors.lastname: Kanouni
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Beverly
authors.initials: B
authors.lastname: Knight
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Lawson
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Taylor
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Phong
authors.initials: P
authors.lastname: Vu
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Wyrick
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D001665:Binding Sites; D003094:Collagen / Q000009:adverse effects; D004285:Dogs; D055808:Drug Discovery; D005260:Female; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse