5 research outputs found
No up-regulation of the phosphatidylethanolamine N-methyltransferase pathway and choline production by sex hormones in cats
From in Silico Discovery to Intracellular Activity: Targeting JNKâProtein Interactions with Small Molecules
The JNKâJIP1 interaction represents an attractive
target
for the selective inhibition of JNK-mediated signaling. We report
a virtual screening (VS) workflow, based on a combination of three-dimensional
shape and electrostatic similarity, to discover novel scaffolds for
the development of non-ATP competitive inhibitors of JNK targeting
the JNKâJIP interaction. Of 352 (0.13%) compounds selected
from the NCI Diversity Set, more than 22% registered as hits in a
biochemical kinase assay. Several compounds discovered to inhibit
JNK activity under standard kinase assay conditions also impeded JNK
activity in HEK293 cells. These studies led to the discovery that
the lignan (â)-zuonin A inhibits JNKâprotein interactions
with a selectivity of 100-fold over ERK2 and p38 MAPKα. These
results demonstrate the utility of a virtual screening protocol to
identify novel scaffolds for highly selective, cell-permeable inhibitors
of JNKâprotein interactions