ArticlePloS one2016
Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 37 citations in OpenAlex.
- Discovery of Potent FGFR2/3 Inhibitors to Overcome Mutation Resistance and Treat Achondroplasia.ACS medicinal chemistry letters · 2025Article
- Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.Molecular cancer · 2024Review
- Alpinumisoflavone against cancer pro-angiogenic targets: In silico, In vitro, and In ovo evaluation.Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2022Article
- Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants.Communications chemistry · 2022Article
- Article
- Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance.Scientific reports · 2021Article
- Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance.British journal of cancer · 2021Review
- FGFR-TKI resistance in cancer: current status and perspectives.Journal of hematology & oncology · 2021Review
- Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase.International journal of molecular sciences · 2020Article
- Review
- Structural basis for DNA recognition by FOXC2.Nucleic acids research · 2019Article
- Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.Cells · 2019Article
- DNA-binding properties of FOXP3 transcription factor.Acta biochimica et biophysica Sinica · 2017Article
- Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site.Biochemistry · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.
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