The c-Jun N-terminal kinases (JNK-1, -2, an
d -3) are members of the mitogen activate
d protein (MAP)kinase family of enzymes. They are activate
d in response to certain cytokines, as well as by cellular stressesinclu
ding chemotoxins, peroxi
des, an
d irra
diation. They have been implicate
d in the pathology of a varietyof
different
diseases with an inflammatory component inclu
ding asthma, stroke, Alzheimer's
disease, an
dtype 2
diabetes mellitus. In this work, high-throughput screening i
dentifie
d a JNK inhibitor with an excellentkinase selectivity profile. Using X-ray crystallography an
d biochemical screening to gui
de our lea
doptimization, we prepare
d compoun
ds with inhibitory potencies in the low-
double-
digit nanomolar range,activity in whole cells, an
d pharmacokinetics suitable for in vivo use. The new compoun
ds were over 1000-fol
d selective for JNK-1 an
d -2 over other MAP kinases inclu
ding ERK2, p38
![](/images/gifchars/alpha.gif)
, an
d p38
![](/images/gifchars/<font color=)
delta.gif" BORDER=0 > an
d showe
d littleinhibitory activity against a panel of 74 kinases.