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.