ArticleJournal of the American Chemical Society2016
Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 45 citations in OpenAlex.
- Soft drugs: design principles and topical applications.Nature reviews. Drug discovery · 2026Review
- Tunable Aromatic Sulfoxides and Sulfones as Cysteine-Targeting Warheads: Exploring the Structure-Reactivity Relationship.Journal of medicinal chemistry · 2026Article
- Inhibiting Mrt4-rRNA interaction with fumaramidmycin-based derivatives as an antifungal strategy.Nature communications · 2026Article
- Shaping Antimalarials: A Geometry-First Approach toJournal of medicinal chemistry · 2026Article
- Article
- Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.Nature communications · 2023Article
- Potent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2.Research square · 2022Article
- Reactive chemistry for covalent probe and therapeutic development.Trends in pharmacological sciences · 2022Review
- Dichloro Butenediamides as Irreversible Site-Selective Protein Conjugation Reagent.Angewandte Chemie (International ed. in English) · 2021Article
- Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry.Journal of the American Chemical Society · 2021Article
- 10 years into the resurgence of covalent drugs.Future medicinal chemistry · 2021Article
- Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure.International journal of molecular sciences · 2020Article
- Targeting a Pathogenic Cysteine Mutation: Discovery of a Specific Inhibitor of Y279C SHP2.Biochemistry · 2020Article
- Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.Chemical biology & drug design · 2020Article
- Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles.Nature chemical biology · 2020Article
- Targeted and proteome-wide analysis of metabolite-protein interactions.Current opinion in chemical biology · 2020Review
- The Proteome-Wide Potential for Reversible Covalency at Cysteine.Angewandte Chemie (International ed. in English) · 2019Article
- Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Redox Signaling by Reactive Electrophiles and Oxidants.Chemical reviews · 2018Review
- The Taxonomy of Covalent Inhibitors.Biochemistry · 2018Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics. Here, we describe an approach to confer kinetic selectivity to electrophilic drugs. We show that an analogue of the covalent Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib bearing a fumarate ester electrophile is vulnerable to enzymatic metabolism on a time-scale that preserves rapid and sustained BTK inhibition, while thwarting more slowly accumulating off-target reactivity in cell and animal models. These findings demonstrate that metabolically labile electrophilic groups can endow covalent drugs with kinetic selectivity to enable perturbation of proteins and biochemical pathways with greater precision.
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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.