Screening of subtype-specific activators and inhibitors for diacylglycerol kinase

Diacylglycerol kinase (DGK) is a lipid kinase that converts diacylglycerol (DG) into phosphatidic acid (PA). DG and PA function as lipid messengers contributing to various signalling pathways. Thus, DGK plays a pivotal role in the signalling pathways by maintaining DG and PA levels. For example, DGK delta is involved in diabetes and DGK beta is important for higher brain function including memory and emotion. Recently, we also revealed that the activation of DGK alpha ameliorated diabetic nephropathy (DN) in mice, suggesting that DGK can be therapeutic target. However, there is no commercially available DGK subtype-specific inhibitors or activators. Therefore, in a series of experiment to find DGK subtype-specific inhibitors or activators, we tried to screen novel DGK alpha activators from 9,600 randomly selected compounds by using high-throughput screening we had recently developed. Finally, we obtained two lead compounds for DGK alpha activators, KU-8 and KU-10. Focusing KU-8, we assessed the effect of KU-8 on all mammalian DGKs activities. Thus, KU-8 activates not only DGK alpha but also DGK theta by approximately 20%, and strongly inhibited DGK kappa. In conclusion, KU-8 would be a good lead compound for DGK alpha and DGK theta activators, and useful as a DGK kappa inhibitor.