Discovery of amido-benzisoxazoles as potent c-Kit inhibitors.
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.
Kunz
Roxanne K
RK
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. kunz@amgen.com
Rumfelt
Shannon
S
Chen
Ning
N
Zhang
Dawei
D
Tasker
Andrew S
AS
Bürli
Roland
R
Hungate
Randall
R
Yu
Violeta
V
Nguyen
Yen
Y
Whittington
Douglas A
DA
Meagher
Kristin L
KL
Plant
Matthew
M
Tudor
Yanyan
Y
Schrag
Michael
M
Xu
Yang
Y
Ng
Gordon Y
GY
Hu
Essa
E
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
D000577:Amides; D007555:Isoxazoles; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases