Diacylglycerol kinases (DGKs) are integral components of signal transduction pathways that regulate cell biology through phosphorylation of the ubiquitous secondary messenger diacylglycerol. Emerging clinical evidence supports specific DGK isoforms as promising targets for immuno-oncology because of their critical role in regulating lipid signaling necessary for T cell receptor activation. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to develop selective inhibitors for basic studies and applications in oncology. Here, I will discuss efforts from my group to utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to map druggable sites for each and every member of the DGK superfamily. We use our chemoproteomic strategy to discover an unusual binding mode for the DGK-alpha (DGKA) inhibitor ritanserin, including interactions at the atypical C1 domain distinct from the ATP binding pocket. The prominent binding of ritanserin and its fragment derivatives at the DGKA C1 domain suggests this site is a potential ligand binding hotspot. We will describe our progress on adapting our chemoproteomic strategy for fragment-based screening of novel ligands of DGK C1 domains with the goal of developing high affinity DGKA inhibitors for direct testing in primary human T cells. Collectively, our studies illustrate the power of quantitative chemoproteomics to site-specifically profile protein-small molecule interactions and reveal key druggable sites to develop lipid kinases inhibitors for immuno-oncology.

Chemoproteomic discovery of lipid kinase inhibitors for immuno-oncology

255th National Meeting (2018)

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