Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists
Autor: | Salome Boroda, Maria Niccum, Benjamin Purow, Thurl E. Harris, Vidisha Raje |
---|---|
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Diacylglycerol Kinase Ritanserin Pyrimidinones Pharmacology Biochemistry Article 03 medical and health sciences Adenosine Triphosphate medicine Humans Enzyme Inhibitors Kinase activity Receptor Diacylglycerol Kinase Alpha Protein kinase C 5-HT receptor Diacylglycerol kinase Chemistry HEK 293 cells Kinetics Thiazoles HEK293 Cells 030104 developmental biology Electrophoresis Polyacrylamide Gel HeLa Cells medicine.drug |
Zdroj: | Biochemical Pharmacology. 123:29-39 |
ISSN: | 0006-2952 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |