Potent and selective pyrazole-based inhibitors of B-Raf kinase.
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.
Hansen
Joshua D
JD
Lead Optimization, Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA. josh.hansen@arraybiopharma.com
Grina
Jonas
J
Newhouse
Brad
B
Welch
Mike
M
Topalov
George
G
Littman
Nicole
N
Callejo
Michele
M
Gloor
Susan
S
Martinson
Matthew
M
Laird
Ellen
E
Brandhuber
Barbara J
BJ
Vigers
Guy
G
Morales
Tony
T
Woessner
Rich
R
Randolph
Nikole
N
Lyssikatos
Joseph
J
Olivero
Alan
A
D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases