ArticleBiochemistry2018
Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Article
- A Perspective on the Strategic Application of Deconstruction-Reconstruction in Drug Discovery.Journal of medicinal chemistry · 2025Review
- Diacylglycerol kinase is a keystone regulator of signaling relevant to the pathophysiology of asthma.American journal of physiology. Lung cellular and molecular physiology · 2024Review
- Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Chemoproteomic Profiling of Geranyl Pyrophosphate-Binding Proteins.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Identification of ritanserin analogs that display DGK isoform specificity.Biochemical pharmacology · 2022Article
- Advances in chemical proteomic evaluation of lipid kinases-DAG kinases as a case study.Current opinion in chemical biology · 2021Review
- Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1.International journal of molecular sciences · 2021Review
- Chemical Proteomic Profiling of the Interacting Proteins of Isoprenoid Pyrophosphates.Analytical chemistry · 2020Article
- The role of diacylglycerol kinases in allergic airway disease.Current opinion in pharmacology · 2020Review
- Spatiotemporal control of phosphatidic acid signaling with optogenetic, engineered phospholipase Ds.The Journal of cell biology · 2020Article
- Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering.Nature chemical biology · 2020Article
- DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases.International journal of molecular sciences · 2019Review
- Activity-Based Kinome Profiling Using Chemical Proteomics and ATP Acyl Phosphates.Current protocols in chemical biology · 2019Article
- Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells.Molecular pharmacology · 2018Article
- Isoform-selective activity-based profiling of ERK signaling.Chemical science · 2018Article
- Deciphering T Cell Immunometabolism with Activity-Based Protein Profiling.Current topics in microbiology and immunologyReview
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Diacylglycerol kinases (DGKs) regulate lipid metabolism and cell signaling through ATP-dependent phosphorylation of diacylglycerol to biosynthesize phosphatidic acid. Selective chemical probes for studying DGKs are currently lacking and are needed to annotate isoform-specific functions of these elusive lipid kinases. Previously, we explored fragment-based approaches to discover a core fragment of DGK-α (DGKα) inhibitors responsible for selective binding to the DGKα active site. Here, we utilize quantitative chemical proteomics to deconstruct widely used DGKα inhibitors to identify structural regions mediating off-target activity. We tested the activity of a fragment (RLM001) derived from a nucleotide-like region found in the DGKα inhibitors R59022 and ritanserin and discovered that RLM001 mimics ATP in its ability to broadly compete at ATP-binding sites of DGKα as well as >60 native ATP-binding proteins (kinases and ATPases) detected in cell proteomes. Equipotent inhibition of activity-based probe labeling by RLM001 supports a contiguous ligand-binding site composed of C1, DAGKc, and DAGKa domains in the DGKα active site. Given the lack of available crystal structures of DGKs, our studies highlight the utility of chemical proteomics in revealing active-site features of lipid kinases to enable development of inhibitors with enhanced selectivity against the human proteome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.