Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach.
Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.
Smith
R A
RA
Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA. roger.smith.b@bayer.com
Barbosa
J
J
Blum
C L
CL
Bobko
M A
MA
Caringal
Y V
YV
Dally
R
R
Johnson
J S
JS
Katz
M E
ME
Kennure
N
N
Kingery-Wood
J
J
Lee
W
W
Lowinger
T B
TB
Lyons
J
J
Marsh
V
V
Rogers
D H
DH
Swartz
S
S
Walling
T
T
Wild
H
H
D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D014508:Urea; D019908:Proto-Oncogene Proteins c-raf