ArticleOncotarget2018
Structural insights into drug development strategy targeting EGFR T790M/C797S.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 42 citations in OpenAlex.
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- Synthesis, comprehensive in silico studies, and cytotoxicity evaluation of novel quinazolinone derivatives as potential anticancer agents.Scientific reports · 2025Article
- Anticancer activity, phytochemical investigation and molecular docking insights of Citrullus colocynthis (L.) fruits.Scientific reports · 2023Article
- Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors.Methods in enzymology · 2023Article
- L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment.Discover oncology · 2022Article
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- New Cladiellin-Type Diterpenoids from the South China Sea Soft CoralMarine drugs · 2022Article
- Systematic analysis and molecular profiling of EGFR allosteric inhibitor cross-reactivity across the proto-oncogenic ErbB family kinases by integrating dynamics simulation, energetics calculation and biochemical assay.European biophysics journal : EBJ · 2022Article
- Icotinib, Almonertinib, and Olmutinib: A 2D Similarity/Docking-Based Study to Predict the Potential Binding Modes and Interactions into EGFR.Molecules (Basel, Switzerland) · 2021Article
- Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension.Advances in experimental medicine and biology · 2021Review
- How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRMolecules (Basel, Switzerland) · 2020Article
- Water-Soluble Pristine COxidative medicine and cellular longevity · 2020Article
- Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants.ACS chemical biology · 2019Article
- Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death.Cancers · 2019Article
- C797S Resistance: The Undruggable EGFR Mutation in Non-Small Cell Lung Cancer?ACS medicinal chemistry letters · 2018Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.
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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.