ArticleJournal of the American Chemical Society2019
A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 90 citations in OpenAlex.
- Detecting protein higher-order structural changes using kinase as a phospho-labeler.Cell reports methods · 2026Article
- Modular Rh-Catalyzed Synthesis and Biological Profiling of Diverse Pentafluorobenzenesulfonamide Reactive Fragments.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- High-throughput discovery and characterisation of pentafluorobenzene sulfonamide modifiers of Aurora A kinase.RSC chemical biology · 2026Article
- Selective Inhibitor of Protein Kinase PKN3 Generated by Conjugation of a Structurally Optimized BumpedMolecules (Basel, Switzerland) · 2026Article
- COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale.Nature communications · 2025Article
- Gas Phase Separation of Modified Peptides for Activity-Based Protein Profiling.Analytical chemistry · 2025Article
- Chemoproteomics-EnabledJournal of the American Chemical Society · 2025Article
- cAmbly: A non-toxic cell-penetrating peptide derived from Amblyomin-X with targeted delivery to mitochondrial and cytoplasmic proteins.PloS one · 2025Article
- Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells.Nature chemistry · 2024Article
- Dual-Probe Activity-Based Protein Profiling Reveals Site-Specific Differences in Protein Binding of EGFR-Directed Drugs.ACS chemical biology · 2024Article
- Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.Journal of the American Chemical Society · 2024Article
- Chemical Proteomics-Guided Discovery of Covalent Ligands for Cancer Proteins.Annual review of cancer biology · 2024Article
- Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors.Nature chemical biology · 2024Article
- Accelerating multiplexed profiling of protein-ligand interactions: High-throughput plate-based reactive cysteine profiling with minimal input.Cell chemical biology · 2024Article
- Metal-Mediated Ligand Affinity Chemistry (MLAC).Methods in molecular biology (Clifton, N.J.) · 2024Article
- Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead.RSC chemical biology · 2023Article
- AzidoTMT Enables Direct Enrichment and Highly Multiplexed Quantitation of Proteome-Wide Functional Residues.Journal of proteome research · 2023Article
- Technologies for Direct Detection of Covalent Protein-Drug Adducts.Pharmaceuticals (Basel, Switzerland) · 2023Review
- MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
Despite recent clinical successes for irreversible drugs, potential toxicities mediated by unpredictable modification of off-target cysteines represents a major hurdle for expansion of covalent drug programs. Understanding the proteome-wide binding profile of covalent inhibitors can significantly accelerate their development; however, current mass spectrometry strategies typically do not provide a direct, amino acid level readout of covalent activity for complex, selective inhibitors. Here we report the development of CITe-Id, a novel chemoproteomic approach that employs covalent pharmacologic inhibitors as enrichment reagents in combination with an optimized proteomic platform to directly quantify dose-dependent binding at cysteine-thiols across the proteome. CITe-Id analysis of our irreversible CDK inhibitor THZ1 identified dose-dependent covalent modification of several unexpected kinases, including a previously unannotated cysteine (C840) on the understudied kinase PKN3. These data streamlined our development of JZ128 as a new selective covalent inhibitor of PKN3. Using JZ128 as a probe compound, we identified novel potential PKN3 substrates, thus offering an initial molecular view of PKN3 cellular activity. CITe-Id provides a powerful complement to current chemoproteomic platforms to characterize the selectivity of covalent inhibitors, identify new, pharmacologically addressable cysteine-thiols, and inform structure-based drug design programs.
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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.