{"doi":"10.64898/2025.12.09.692983","title":"Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity","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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556929,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1457050,"name":"Surya Pravo Mookherjee","orcid":null,"position":1,"is_corresponding":false},{"id":842560,"name":"Claire C. Weckerly","orcid":"0000-0003-2368-8429","position":2,"is_corresponding":false},{"id":498723,"name":"Adam H. Libby","orcid":null,"position":3,"is_corresponding":false},{"id":338345,"name":"Aizhen Xiao","orcid":null,"position":4,"is_corresponding":false},{"id":1107752,"name":"Yunge Zhao","orcid":"0000-0001-5757-357X","position":5,"is_corresponding":false},{"id":1457051,"name":"Shailja Vaidya","orcid":null,"position":6,"is_corresponding":false},{"id":1082613,"name":"AeRyon Kim","orcid":"0000-0001-8016-1944","position":7,"is_corresponding":false},{"id":715664,"name":"Zhihong Li","orcid":"0000-0002-5978-7894","position":8,"is_corresponding":false},{"id":1238825,"name":"Madeleine L. Ware","orcid":null,"position":9,"is_corresponding":false},{"id":1457052,"name":"Michelle Marants","orcid":null,"position":10,"is_corresponding":false},{"id":1457053,"name":"Olivia Murtagh","orcid":null,"position":11,"is_corresponding":false},{"id":1457054,"name":"Wesley J Wolfe","orcid":null,"position":12,"is_corresponding":false},{"id":347742,"name":"Timothy N. J. Bullock","orcid":"0000-0001-6141-3261","position":13,"is_corresponding":false},{"id":336895,"name":"Benjamin Purow","orcid":"0000-0001-7372-6062","position":14,"is_corresponding":false},{"id":245412,"name":"Gerald Hammond","orcid":"0000-0002-6660-3272","position":15,"is_corresponding":false},{"id":1457055,"name":"Ku-Lung Hsu","orcid":null,"position":16,"is_corresponding":false},{"id":1090207,"name":"Minhaj Shaikh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41427359","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}