ArticleNature chemical biology2019
Selective and reversible modification of kinase cysteines with chlorofluoroacetamides.
Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 141 citations in OpenAlex.
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- Chemoselective Reagents for the Traceless Bioreversible Modification of Native Proteins.Bioconjugate chemistry · 2024Article
- Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action.ACS chemical biology · 2024Review
- Simulation of gap junction formation reveals critical role of Cys disulfide redox state in connexin hemichannel docking.Cell communication and signaling : CCS · 2024Article
- Ultra-rapid Electrophilic Cysteine Arylation.Journal of the American Chemical Society · 2023Article
- Chloroacetamide fragment library screening identifies new scaffolds for covalent inhibition of the TEAD·YAP1 interaction.RSC medicinal chemistry · 2023Article
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Corrections and comments
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Authors and funding
25 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.
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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.