Modulators of Diacylglycerol Kinase Activity: A Review of Advances and Challenges

: Catalyzing the conversion of diacylglycerol (DAG) in phosphatidic acid (PA), diacylglycerol kinases (DGKs) play a pivotal role in all the physiological processes modulated by these two bioactive lipids, such as lipid metabolism and immune regulation. Consequently, abnormalities due to a dysregulation of DGK's activity are involved in several pathological contexts, from cancer to autoimmune diseases. Interestingly, ten DGK isoforms with specific structure and expression pattern are present in humans, suggesting nonredundant roles. Despite their potential as therapeutic targets, the possibility of selective DGK pharmacological modulation remains limited to two isoforms. However, the research for DGK isoform-specific modulators is growing, as well as the interest in the structure and functioning of all DGK family members. This review aims to present all the information on DGK modulators, from the literature to patents' databases, starting from what we know about DGK's structure, the key physiological and pathological processes where they are involved and, above all, to understand which are nowadays the possibilities for DGK activation/inhibition. Our aim is to inspire future investigations which could accelerate the discovery of new DGK-targeting compounds.