title: Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists.
abstract: Diacylglycerol kinase alpha (DGKα) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Recently, DGKα was identified as a therapeutic target in various cancers, as well as in immunotherapy. Application of small-molecule DGK inhibitors, R59022 and R59949, induces cancer cell death in vitro and in vivo. The pharmacokinetics of these compounds in mice, however, are poor. Thus, there is a need to discover additional DGK inhibitors not only to validate these enzymes as targets in oncology, but also to achieve a better understanding of their biology. In the present study, we investigate the activity of ritanserin, a compound structurally similar to R59022, against DGKα. Ritanserin, originally characterized as a serotonin (5-HT) receptor (5-HTR) antagonist, underwent clinical trials as a potential medicine for the treatment of schizophrenia and substance dependence. We document herein that ritanserin attenuates DGKα kinase activity while increasing the enzyme's affinity for ATP in vitro. In addition, R59022 and ritanserin function as DGKα inhibitors in cultured cells and activate protein kinase C (PKC). While recognizing that ritanserin attenuates DGK activity, we also find that R59022 and R59949 are 5-HTR antagonists. In conclusion, ritanserin, R59022 and R59949 are combined pharmacological inhibitors of DGKα and 5-HTRs in vitro.
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Salome
authors.initials: S
authors.lastname: Boroda
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Niccum
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Raje
authors.affiliation: Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. Electronic address: bwp5g@virginia.edu.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Purow
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. Electronic address: teh3c@virginia.edu.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D011744:Pyrimidinones / Q000494:pharmacology*; D016713:Ritanserin / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D013844:Thiazoles; D016713:Ritanserin; D000255:Adenosine Triphosphate; C047505:R 59022; D019852:Diacylglycerol Kinase
keywords: Diacylglycerol kinase (DGK); Diacylglycerol kinase inhibitor I (PubChem CID: 3012); Diacylglycerol kinase inhibitor II (PubChem CID: 657356); Ketanserin (PubChem CID: 3822).; Protein kinase C (PKC); R59022; Ritanserin; Ritanserin (PubChem CID: 5074); Serotonin receptor (5-HTR)