2. Academic Validation
  3. Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity

Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity

  • bioRxiv. 2025 Dec 12:2025.12.09.692983. doi: 10.64898/2025.12.09.692983.
Minhaj Shaikh 1,  Surya Pravo Mookherjee 1,  Claire C Weckerly 2,  Adam H Libby 3 4,  Aizhen Xiao 5,  Yunge Zhao 5,  Sagar D Vaidya 1,  AeRyon Kim 6,  Zhihong Li 1,  Madeleine L Ware 1,  Michelle Marants 1,  Olivia L Murtagh 1,  Wesley J Wolfe 1,  Timothy Nj Bullock 6,  Benjamin W Purow 5,  Gerald R V Hammond 2,  Ku-Lung Hsu 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA.
  • 2 Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 3 Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
  • 4 Drug Discovery Center, UVA Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, 22904, USA.
  • 5 Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
  • 6 Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
PMID: 41427359 DOI: 10.64898/2025.12.09.692983
Abstract

Stereoselective recognition is a powerful means to differentiate selective versus non-specific activity of small molecules in complex biological systems. Here, we disclose stereochemically defined, sulfonyltriazole inhibitors of the lipid enzyme diacylglycerol kinase-alpha (DGKα), a key metabolic checkpoint for T cell effector function. Acute treatment with the covalent DGKα inhibitor AHL-7160 recruited endogenous DGKα to the plasma membrane in a stereoselective and isozyme-specific manner. The membrane translocation activity of AHL-7160 correlated with blockade of cellular phosphatidic acid production and potentiation of primary T cell-mediated killing of a glioblastoma cell line. Quantitative chemoproteomics revealed Y669 and K411 as sites of AHL-7160 modification on endogenous DGKα in cells. Extended treatments resulted in proteasome-dependent and proteome-wide selective degradation of DGKα in T cells. Collectively, these findings establish covalent DGKα ligands as potent Molecular Glues with translational potential in immunotherapy.

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