ArticleProceedings of the National Academy of Sciences of the United States of America2014
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed, 178 citations in OpenAlex.
- Systematic Targeting of Protein Complexes with Molecular COUPLrs.Cancer discovery · 2026Article
- AI-Driven discovery and experimental validation of covalent FGFR4 inhibitors for hepatocellular carcinoma.Journal of translational medicine · 2026Article
- Discovery of Covalent Ligands with AlphaFold3.Journal of the American Chemical Society · 2026Article
- Integrative Multi-Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN-2, a Covalent FGFR Inhibitor.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting the BAG2/CHIP axis promotes gastric cancer apoptosis by blocking apoptosome assembly.Frontiers in immunology · 2025Article
- The Landscape of Potential Targeted Treatments and Chemotherapy Efficacy Biomarkers for TNBC.Breast cancer (Dove Medical Press) · 2025Review
- Pharmacological and Biological Targeting of FGFR1 in Cancer.Current issues in molecular biology · 2024Review
- Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors.ACS medicinal chemistry letters · 2024Article
- Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.Cancer medicine · 2024Article
- Developing New Peptides and Peptide-Drug Conjugates for Targeting the FGFR2 Receptor-Expressing Tumor Cells and 3D Spheroids.Biomimetics (Basel, Switzerland) · 2024Article
- Targeting FGFR for cancer therapy.Journal of hematology & oncology · 2024Review
- Expression of fibroblast growth factor receptor 1 correlates inversely with the efficacy of single-agent fibroblast growth factor receptor-specific inhibitors in pancreatic cancer.British journal of pharmacology · 2024Article
- Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology.Journal of translational medicine · 2024Article
- FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.Nature reviews. Clinical oncology · 2024Review
- Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.Journal of hepatology · 2024Article
- Review
- An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2023Review
- A phase I, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib.Clinical and translational science · 2023Article
- Sustained response on sequential anti-FGFR therapy in metastatic gall bladder cancer: a case report and literature review.Journal of cancer research and clinical oncology · 2023Review
- N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics.Nature communications · 2023Article
23 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 10 institutions in 4 countries.
Funding
Abstract
The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
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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.