Boroda Salome, Niccum Maria, Raje Vidisha, Purow Benjamin W, Harris Thurl E
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Biochem Pharmacol. 2017 Jan 1;123:29-39. doi: 10.1016/j.bcp.2016.10.011. Epub 2016 Oct 28.
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.
二酰基甘油激酶α（DGKα）催化二酰基甘油（DAG）转化为磷脂酸（PA）。最近，DGKα被确定为多种癌症以及免疫治疗中的治疗靶点。应用小分子DGK抑制剂R59022和R59949可在体外和体内诱导癌细胞死亡。然而，这些化合物在小鼠体内的药代动力学较差。因此，不仅需要发现更多的DGK抑制剂来验证这些酶作为肿瘤学靶点，还需要更好地了解它们的生物学特性。在本研究中，我们研究了与R59022结构相似的化合物利坦色林对DGKα的活性。利坦色林最初被表征为5-羟色胺（5-HT）受体（5-HTR）拮抗剂，并作为治疗精神分裂症和物质依赖的潜在药物进行了临床试验。我们在此记录，利坦色林在体外可减弱DGKα激酶活性，同时增加该酶对ATP的亲和力。此外，R59022和利坦色林在培养细胞中作为DGKα抑制剂发挥作用，并激活蛋白激酶C（PKC）。在认识到利坦色林可减弱DGK活性的同时，我们还发现R59022和R59949是5-HTR拮抗剂。总之，利坦色林、R59022和R59949在体外是DGKα和5-HTRs的联合药理抑制剂。
