1 research outputs found
From in Silico Discovery to Intracellular Activity: Targeting JNKāProtein Interactions with Small Molecules
The JNKāJIP1 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 JNKāJIP 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 (ā)-zuonin A inhibits JNKāprotein interactions
with a selectivity of 100-fold over ERK2 and p38 MAPKĪ±. These
results demonstrate the utility of a virtual screening protocol to
identify novel scaffolds for highly selective, cell-permeable inhibitors
of JNKāprotein interactions