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Elhalem et al (10-17-20)-ChemRxiv.pdf (1.37 MB)

Design, Synthesis and Characterization of Novel sn-1 Heterocyclic DAGlactones as PKCe Activators

submitted on 17.10.2020, 15:18 and posted on 19.10.2020, 10:57 by Eleonora Elhalem, Ana Bellomo, Mariana Cooke, Antonella Scravaglieri, Larry V. Pearce, Megan Peach, Lucía Gandolfi-Donadío, Marcelo Kazanietz, Maria Julieta Comin

In this study we describe the synthesis and characterization of novel diacylglycerol (DAG)-lactones that bind to protein kinase C (PKC). DAG-lactones proved to be useful templates for the design of potent and selective C1 domain ligands. The ester moiety at sn-1 position, a common feature in this template, is relevant for interaction with the PKC C1 domains, although it represents a labile group susceptible to endogenous esterases. Our studies identified the DAG-lactone 10B12 with an isozazole ring as a nanomolar affinity PKC ligand. This compound shows preferential selectivity for PKCepsilon, and strongly activates actin cytoskeleton reorganization into peripheral ruffles in cancer cells, an effect mediated by PKCepsilon. Therefore, introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC selectivity.


PICT-201-0362 from ANPCyT, Argentina (to M.J.C.)

PICT-2018-N° 01036 from ANPCyT, Argentina (to M.J.C.)

PIP2014-2016 GI from CONICET, Argentina (to M.J.C.)

R01-ES026023 from NIH (to M.G.K.)

R01-CA189765 from NIH (to M.G.K.)

R01-CA196232 from NIH (to M.G.K.)

HHSN261200800001E contract from Frederick National Laboratory for Cancer Research, National Institutes of Health (M.L.P.)


Email Address of Submitting Author


University of Pennsylvania



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflicts of interest