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Characterization of a repurposed agent as a potent inhibitor of DGKa (1062.1)
Author(s) -
Boroda Salome,
Harris Thurl,
Purow Benjamin,
Floyd Desiree
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1062.1
Subject(s) - diacylglycerol kinase , phosphatidic acid , chemistry , kinase , glioblastoma , cancer research , pharmacology , biochemistry , protein kinase c , medicine , phospholipid , membrane
Diacylglycerol Kinases (DGKs) catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). DGK‐mediated increases in PA concentrations have been found to affect pro‐cancer growth and survival pathways such as the mTORC1 pathway and the HIF ‐1α pathway. As a consequence, the DGKs are promising therapeutic targets for a large range of cancers. Specifically, the attenuation of DGKα by a small molecule inhibitor, R59022, has shown to dramatically decrease cell survival in glioblastoma models (Dominguez et al, 2013). R59022 has only been used in laboratories and completion of clinical trials could take years before its approval for use in humans. Our database searches have revealed a compound similar in structure to R59022 which we sought to repurpose for the inhibition of DGKα. We purified DGKα from mammalian 293 T cells using affinity chromatography and employed both liposome and micelle assays to measure the effects of this compound (which we term compound R) on DGKα activity. We showed that compound R is a strong uncompetitive inhibitor of DGKα with substantially greater potency than R59022. Taken together, our data suggest that compound R could serve as a viable therapeutic agent in targeting glioblastoma. Grant Funding Source : Supported by: National Institute of Health and University of Virginia