ArticleJournal of medicinal chemistry2020
Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
Article in Journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- In Pursuit of Enduring Inactivation: A Perspective on the Development and Study of Irreversible-Covalent Inhibitors.Biochemistry · 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
- Mutant-Selective Binding ofInternational journal of molecular sciences · 2026Article
- Novel Adenine-Hydrazone Hybrids Against Human Lung Adenocarcinoma (A549): Design, Synthesis, Cellular Mechanistic Investigation and Molecular Docking Studies.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.Journal of chemical information and modeling · 2026Article
- Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.ACS medicinal chemistry letters · 2026Article
- 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
- Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.Journal of medicinal chemistry · 2024Article
- Article
- Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.Communications chemistry · 2024Article
- Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors.ACS omega · 2024Article
- Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.Research square · 2023Article
- Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.ACS medicinal chemistry letters · 2023Article
- Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents.Journal of chemical information and modeling · 2023Article
- Imidazole: Synthesis, Functionalization and Physicochemical Properties of a Privileged Structure in Medicinal Chemistry.Molecules (Basel, Switzerland) · 2023Review
- "From molecular to clinic": The pivotal role of CDC42 in pathophysiology of human papilloma virus related cancers and a correlated sensitivity of afatinib.Frontiers in immunology · 2023Article
- Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors.Methods in enzymology · 2023Article
- Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448).ACS medicinal chemistry letters · 2022Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "αC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.
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