ArticleCommunications chemistry2024
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.
Article in Communications chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Towards better outcomes for epidermal growth factor receptor L858R+ lung cancer patients: mutant-selective allosteric inhibitors and the potential for double-drugging.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Epidermal Growth Factor Receptor as a Model Drug Target for Scrutinizing the Status Quo in Drug Discovery and Chemical Biology.ACS bio & med chem Au · 2026Review
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- A novel approach for enhancing the potency of kinase inhibitors using topological water networks.Journal of cheminformatics · 2026Article
- Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.ACS medicinal chemistry letters · 2026Article
- Discovery of Supra-Bivalent GSK3β Inhibitory Peptides Containing an ATP-Mimetic Amino Acid.Journal of the American Chemical Society · 2026Article
- Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in cell and developmental biology · 2026Review
- Article
- A comprehensive benchmarking of the AlphaFold3 for predicting biomacromolecules and their interactions.Briefings in bioinformatics · 2025Article
- Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.Journal of medicinal chemistry · 2025Article
- Structure-Activity Relationships of Inactive-Conformation Binding EGFR Inhibitors: Linking the ATP and Allosteric Pockets.Archiv der Pharmazie · 2025Article
- Ascertaining a Structural Basis in Drug Discovery and Development.Journal of medicinal chemistry · 2025Article
- A molecular dynamics protocol for rapid prediction of EGFR overactivation and its application to the rare mutations S768I, S768N, D761N.Computational and structural biotechnology journal · 2025Article
- Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.Journal of medicinal chemistry · 2024Article
- Demystifying Functional Parameters for Irreversible Enzyme Inhibitors.Journal of medicinal chemistry · 2024Article
- Exploring acenocoumarol and silodosin in non-small cell lung cancer: Insights into EGFR-linked signaling mechanisms.F1000Research · 2024Article
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Authors and funding
20 authors.
Funding
Abstract
Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.
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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.