title: Discovery of amido-benzisoxazoles as potent c-Kit inhibitors.
abstract: Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. kunz@amgen.com
authors: Roxanne K
authors: RK
authors: Kunz
authors: Shannon
authors: S
authors: Rumfelt
authors: Ning
authors: N
authors: Chen
authors: Dawei
authors: D
authors: Zhang
authors: Andrew S
authors: AS
authors: Tasker
authors: Roland
authors: R
authors: Bürli
authors: Randall
authors: R
authors: Hungate
authors: Violeta
authors: V
authors: Yu
authors: Yen
authors: Y
authors: Nguyen
authors: Douglas A
authors: DA
authors: Whittington
authors: Kristin L
authors: KL
authors: Meagher
authors: Matthew
authors: M
authors: Plant
authors: Yanyan
authors: Y
authors: Tudor
authors: Michael
authors: M
authors: Schrag
authors: Yang
authors: Y
authors: Xu
authors: Gordon Y
authors: GY
authors: Ng
authors: Essa
authors: E
authors: Hu
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
chemical_list: D000577:Amides; D007555:Isoxazoles; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases