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The Repurposing of Ritanserin for the Inhibition of Diacylglycerol Kinase Alpha (DGKα), a Novel Therapeutic Target in Glioblastoma Multiforme (GBM)
Author(s) -
Boroda Salome,
Harris Thurl E.,
Purow Benjamin W.
Publication year - 2016
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.30.1_supplement.937.5
Subject(s) - ritanserin , diacylglycerol kinase , in vivo , pharmacology , chemistry , antagonist , in vitro , cancer research , receptor , medicine , kinase , biology , biochemistry , receptor antagonist , protein kinase c , microbiology and biotechnology
Diacylglycerol Kinase α (DGKα) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Recent work has demonstrated that DGKα activity is at a central tumorigenic node and the attenuation of its activity by a small molecule inhibitor, R59022, has shown promising results in countering glioblastoma multiforme (GBM) growth both in vitro and in vivo (Dominguez, et al , 2013). Until recently, R59022 and R59949 have been the only described inhibitors of DGKα. We have identified a serotonin receptor antagonist, Ritanserin, which is almost structurally identical to R59022. Our data show that Ritanserin is a more potent inhibitor of DGKα activity than R59022 in vitro . We have additionally investigated the specificity of Ritanserin for DGKα over other mammalian DGKs, and the affinity of R59022 for serotonin receptors. Since Ritanserin has previously been used clinically, and shown to have a low incidence of adverse side‐effects, we believe that it could be a viable therapeutic agent for treatment of GBM. Additionally, our work sets the stage for the development for more potent DGKα inhibitors. Support or Funding Information R01 1R01DK101946 to T.E.H, Wanger Fellowship Award, N.I.H Pharmacology graduate student training grant