ArticleJournal of the American Chemical Society2022
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4.
Article in Journal of the American Chemical Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 35 citations in OpenAlex.
- Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments.Chembiochem : a European journal of chemical biology · 2026Article
- Chiral methionine oxidation reagents reveal stereospecific proteome modifications.bioRxiv : the preprint server for biology · 2026Article
- Proteomic Profiling of Oxidative Stress Response Proteins with a Methionine Sulfoxide-Inspired Activity-Based Probe.JACS Au · 2026Article
- CySP3-96 Enables Scalable, Streamlined, and Low-Cost Sample Preparation for Cysteine Chemoproteomic Applications.Molecular & cellular proteomics : MCP · 2025Article
- Light-Activated Reactivity of Nitrones with Amino Acids and Proteins.Angewandte Chemie (International ed. in English) · 2025Article
- Activity-Based Protein Profiling for Functional Cysteines and Protein Target Identification.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Ligand discovery by activity-based protein profiling.Cell chemical biology · 2024Review
- Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.Nature chemical biology · 2024Article
- Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics.Communications chemistry · 2024Article
- Chemoproteomics, A Broad Avenue to Target Deconvolution.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Mapping the Evolution of Activity-Based Protein Profiling: A Bibliometric Review.Advanced pharmaceutical bulletin · 2023Article
- Cysteine and methionine oxidation in thrombotic disorders.Current opinion in chemical biology · 2023Review
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 2 countries.
Funding
Abstract
Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.
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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.