ArticleACS medicinal chemistry letters2023
Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.
Article in ACS medicinal chemistry letters, 2023. 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, 17 citations in OpenAlex.
- Chemical Profiling and Scaffold-Based Drug-Discovery Analysis of Bioactive Compounds fromJournal of chemical information and modeling · 2026Article
- Acquired resistance of cancer therapies: Mechanisms and perspectives.Chinese medical journal · 2026Review
- Charting the blueprint: a bibliometric analysis reveals future strategies in lung cancer targeted therapy (2003-2025).Journal of thoracic disease · 2026Article
- Case Report: Short-term disease control with subsequent icotinib therapy in EGFR L858R/C797S, T790M-negative lung adenocarcinoma after osimertinib resistance.Frontiers in oncology · 2026Article
- Resistance to third-generation EGFR TKIs - what can be expected from the fourth-generation?Cancer drug resistance (Alhambra, Calif.) · 2026Review
- Article
- Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Mechanism of Dahuang-Dangshen drug pairs in the treatment of HCC based on network pharmacology, bioinformatics, molecular docking and experimental verification.Medical oncology (Northwood, London, England) · 2025Article
- Development of indole hybrids for potential lung cancer treatment-part I: nitrogen-containing six-membered aromatic heterocycles.Future medicinal chemistry · 2025Review
- Rhodanine-Piperazine Hybrids as Potential VEGFR, EGFR, and HER2 Targeting Anti-Breast Cancer Agents.International journal of molecular sciences · 2024Article
- Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.
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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.