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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

preprint
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.


Funding

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.)

History

Email Address of Submitting Author

marcelog@pennmedicine.upenn.edu

Institution

University of Pennsylvania

Country

USA

ORCID For Submitting Author

0000-0001-8779-017X

Declaration of Conflict of Interest

No conflicts of interest

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