posted on 2021-07-19, 17:49authored byEleonora Elhalem, Ana Bellomo, Mariana Cooke, Antonella Scravaglieri, Larry V. Pearce, Megan L. Peach, Lucía Gandolfi Donadío, Marcelo G. Kazanietz, María J. Comin
DAG-lactones represent useful templates
for the design of potent
and selective C1 domain ligands for PKC isozymes. The ester moiety
at the sn-1 position, a common feature in this template,
is relevant for C1 domain interactions, but it represents a labile
group susceptible to endogenous esterases. An interesting challenge
involves replacing the ester group of these ligands while still maintaining
biological activity. Here, we present the synthesis and functional
characterization of novel diacylglycerol-lactones containing heterocyclic
ring substituents at the sn-1 position. Our results
showed that the new compound 10B12, a DAG-lactone with
an isoxazole ring, binds PKCα and PKCε with nanomolar
affinity. Remarkably, 10B12 displays preferential selectivity
for PKCε translocation in cells and induces a PKCε-dependent
reorganization of the actin cytoskeleton into peripheral ruffles in
lung cancer cells. We conclude that introducing a stable isoxazole
ring as an ester surrogate in DAG-lactones emerges as a novel structural
approach to achieve PKC isozyme selectivity.