ArticleCancer discovery2023
RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 106 citations in OpenAlex.
- Recurrent Resistance Mutations to Lirafugratinib Inform Treatment Sequencing in FGFR2-Driven Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- 2Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Review
- Landscape of acquired resistance alterations in gastrointestinal malignancies after genomically targeted therapy.Journal of gastrointestinal oncology · 2026Article
- Substrate-Derived Peptides for Selective Covalent Inhibition of Protein Tyrosine Kinases.ACS chemical biology · 2026Article
- Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations.Nature communications · 2026Article
- Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.JCO precision oncology · 2026Review
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Chemical adaptation: bridging synthetic chemistry with drug development.Science China. Life sciences · 2026Review
- Structure-Based Design and Optimization of Novel, Potent and Selective Covalent FGFR2/3 Inhibitors with a Tricyclic Core.Journal of medicinal chemistry · 2026Article
- Substrate-derived peptides for selective covalent inhibition of protein tyrosine kinases.bioRxiv : the preprint server for biology · 2026Article
- PI3Kα Inhibitor and Degrader Inavolisib Can Co-opt FGFR2 to Enhance Responses in Patients with PIK3CA-Mutated Solid Tumors and in Preclinical Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Research on Targeted Therapy for Malignant Tumors of the Biliary Tract.OncoTargets and therapy · 2026Review
- Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations.Nature genetics · 2026Article
- Cholangiocarcinoma 2026: status quo, unmet needs and priorities.Nature reviews. Gastroenterology & hepatology · 2026Review
- Identification of small molecule inhibitors targeting FGFR through molecular docking-based screening.Frontiers in oncology · 2026Article
- Unraveling the FGFR-RNA splicing axis: Mechanisms, oncogenic crosstalks and innovations for therapeutic purpose.Acta pharmaceutica Sinica. B · 2026Review
- Treatment of biliary tract cancer - essentials for clinical practice.Frontiers in oncology · 2026Review
- FGFR Aberrations in Solid Tumors: Mechanistic Insights and Clinical Translation of Targeted Therapies.Cancers · 2025Review
- Pancreatic cancer in 2025: Have we found a solution?World journal of gastroenterology · 2025Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
31 authors at 8 institutions in 2 countries.
Funding
Abstract
Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.
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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.