The discovery of potent cRaf1 kinase inhibitors.
A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway.
Lackey
K
K
Glaxo Wellcome, Inc., Research Triangle Park, NC 27709, USA. kel8725@glaxowellcome.com
Cory
M
M
Davis
R
R
Frye
S V
SV
Harris
P A
PA
Hunter
R N
RN
Jung
D K
DK
McDonald
O B
OB
McNutt
R W
RW
Peel
M R
MR
Rutkowske
R D
RD
Veal
J M
JM
Wood
E R
ER
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D019908:Proto-Oncogene Proteins c-raf