ArticleACS chemical biology2015
DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Structural basis for MEKK2 dimerization and substrate recognition.Nature communications · 2025Article
- The role of descriptors extracted from ligand-target interaction to improve conventional QSAR model performance in the realm of angiogenesis receptor modulation to fight cancer.Future medicinal chemistry · 2025Article
- Molecular docking and dynamics in protein serine/threonine kinase drug discovery: advances, challenges, and future perspectives.Frontiers in pharmacology · 2025Review
- Multiple allostery in the regulation of PDGFR beta kinase activities.Acta biochimica et biophysica Sinica · 2024Article
- Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.Cancer medicine · 2024Article
- Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma.British journal of cancer · 2022Article
- Structure-based design of a dual-warhead covalent inhibitor of FGFR4.Communications chemistry · 2022Article
- Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors.Communications chemistry · 2022Article
- Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance.Scientific reports · 2021Article
- FGFR-TKI resistance in cancer: current status and perspectives.Journal of hematology & oncology · 2021Review
- FGFR4: A promising therapeutic target for breast cancer and other solid tumors.Pharmacology & therapeutics · 2020Review
- FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis.Cell death and differentiation · 2019Article
- Review
- Designed mono- and di-covalent inhibitors trap modeled functional motions for Trypanosoma cruzi proline racemase in crystallography.PLoS neglected tropical diseases · 2018Article
- Computational Simulation Studies on the Binding Selectivity of 1-(1H-Benzimidazol-5-yl)-5-aminopyrazoles in Complexes with FGFR1 and FGFR4.Molecules (Basel, Switzerland) · 2018Article
- Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.eLife · 2017Article
- Detection of Ligand-induced Conformational Changes in the Activation Loop of Aurora-A Kinase by PELDOR Spectroscopy.ChemistryOpen · 2016Article
- Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay.Scientific reports · 2016Article
- Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.PloS one · 2016Article
- Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase.Nature communications · 2015Article
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Authors and funding
10 authors.
Funding
Abstract
Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN-2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate-keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2.
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