ArticleNature communications2024
Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Multifaceted Small Molecules as Enzyme Modulators: Cases of Drug Discovery/Repurposing Illustrating Nature's Pragmatism.BioMed research international · 2026Review
- Targeting the Reactive Proteome: Recent Advances in Activity-Based Protein Profiling and Probe Design.Biomolecules · 2025Review
- Activation of enzymatic catalysis via nucleic acid hybridization affords synergistic coupling of specificity, potency, and signal amplification.Nature communications · 2025Article
- Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.Archives of pharmacal research · 2025Review
- Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor.Journal of medicinal chemistry · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- Key advances in the development of reversible covalent inhibitors.Future medicinal chemistry · 2025Article
- Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.Nature communications · 2024Article
Corrections and comments
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Authors and funding
20 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge. These reversible warheads have a complex and cyclic structure with optional chirality center and tailored steric and electronic properties. To validate our proof-of-concept, we modified acrylamide-based covalent inhibitors of c-Jun N-terminal kinases (JNKs). We show that the cyclic warheads have high resilience against off-target thiols. Additionally, the binding affinity, residence time, and even JNK isoform specificity can be fine-tuned by adjusting the substitution pattern or using divergent and orthogonal synthetic elaboration of the warhead. Taken together, the cyclic warheads presented in this study will be a useful tool for medicinal chemists for the deliberate design of safer and functionally fine-tuned covalent inhibitors.
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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 Socratic graph.