ArticleChemMedChem2024
Structural Analysis of the Macrocyclic Inhibitor BI-4020 Binding to EGFR Kinase.
Article in ChemMedChem, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 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
- Dual Targeting of DNA and EGFR by ZYH005 Induces DNA Damage and Mitotic Catastrophe in Glioblastoma.MedComm · 2026Article
- Elucidating the role of the T790M mutation in BLU-945 selectivity for mutant EGFR: structural and energetic insights.Journal of computer-aided molecular design · 2026Article
- Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.ACS medicinal chemistry letters · 2026Article
- Resistance mutations and the blood-brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer.Acta pharmaceutica Sinica. B · 2025Review
- Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors.Methods in enzymology · 2023Article
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Authors and funding
5 authors.
Funding
Abstract
A novel macrocyclic inhibitor of mutant EGFR (BI-4020) has shown promise in pre-clinical studies of T790M and C797S drug-resistant non-small cell lung cancer. To better understand the molecular basis for BI-4020 selectivity and potency, we have carried out biochemical activity assays and structural analysis with X-ray crystallography. Biochemical potencies agree with previous studies indicating that BI-4020 is uniquely potent against drug-resistant L858R/T790M and L858R/T790M/C797S variants. X-ray structures with wild-type (2.4 Å) and T790M/V948R (3.1 Å) EGFR kinase domains show that BI-4020 is likely rendered selective due to interactions with the kinase domain hinge region as well as T790M, akin to Osimertinib. Additionally, BI-4020 is also rendered more potent due to its constrained macrocycle geometry as well as additional H-bonds to conserved K745 and T845 residues in both active and inactive conformations. These findings taken together show how this novel macrocyclic inhibitor is both highly potent and selective for mutant EGFR in a reversible mechanism and motivate structure-inspired approaches to developing targeted therapies in medicinal oncology.
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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.