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Dual Activities of Ritanserin and R59022 as DGKα Inhibitors and Serotonin Receptor Antagonists

Dual Activities of Ritanserin and R59022 as DGKα Inhibitors and Serotonin Receptor Antagonists

Salome Boroda, Maria Niccum, Vidisha Raje, Benjamin W Purow, Thurl E Harris

Biochem Pharmacol. 2017 Jan 1;123:29-39.

PMID: 27974147

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP120166690-A	Diacylglycerol Kinase Inhibitor II		120166-69-0	Price
AP93076892-A	Diacylglycerol Kinase Inhibitor I		93076-89-2	Price

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