Abstract 681: Targeting diacylglycerol kinases for immuno-oncology

Abstract

Abstract Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through phosphorylation of the ubiquitous secondary messenger diacylglycerol. Emerging clinical evidence supports DGK-alpha (DGKA) as a promising target for cancer immunotherapy because of its critical role in regulating lipid signaling necessary for proper T cell activation. Methods for direct evaluation of DGK activity in native biologic systems are lacking and needed to develop chemical probes for studying isoform-specific functions. Here, I will discuss efforts from my group to utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to map previously undefined ATP- and small molecule-binding sites of representative members from all subtypes of the DGK family. We use our chemical proteomics strategy to discover an unusual binding mode for DGKA inhibitors, including interactions at a novel binding site remote from the ATP binding pocket. I will also describe our efforts towards discovery of new lead inhibitors for future development of highly potent and selective DGKA inhibitors. Collectively, our studies illustrate the power of chemical proteomics to site-specifically profile protein-small molecule interactions and reveal key ligand binding sites for selective inactivation of the DGK family of lipid kinases. Citation Format: Ku-Lung Hsu, Hsu Lab at the University of Virginia. Targeting diacylglycerol kinases for immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 681.