ArticleACS medicinal chemistry letters2019
Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4.
Article in ACS medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 9 citations in OpenAlex.
- Review
- Efficient acrylamide adduct formation suggests dual applications of ReAIV L-asparaginase.Amino acids · 2026Article
- FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities.Theranostics · 2026Review
- Cytotoxic and senescence-inducing effects of BLU554 in pancreatic ductal adenocarcinoma: an in vitro study.BMC cancer · 2025Article
- Anti-hepatocellular carcinoma activities of novel hydrazone derivativesRSC advances · 2024Article
- Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Article
- Current progress in cancer treatment by targeting FGFR signaling.Cancer biology & medicine · 2023Article
- 6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Structure-based design of a dual-warhead covalent inhibitor of FGFR4.Communications chemistry · 2022Article
- Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2.Angewandte Chemie (International ed. in English) · 2021Article
- Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors.ACS medicinal chemistry letters · 2021Article
- Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets.Frontiers in pharmacology · 2021Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberration in FGFR4 signaling drives carcinogenesis and progression in a subset of hepatocellular carcinoma (HCC) patients, thereby making FGFR4 an attractive molecular target for this disease. Selective FGFR4 inhibition can be achieved through covalently targeting a poorly conserved cysteine residue in the FGFR4 kinase domain. We report mass spectrometry assays and cocrystal structures of FGFR4 in covalent complex with the clinical candidate BLU554 and with a series of four structurally related inhibitors that define the inherent reactivity and selectivity profile of these molecules. We further reveal the structure of FGFR1 with one of our inhibitors and show that off-target covalent binding can occur through an alternative conformation that supports targeting of a cysteine conserved in all members of the FGFR family. Collectively, we propose that rotational freedom, steric hindrance, and protein dynamics explain the exceptional selectivity profile of BLU554 for targeting FGFR4.
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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.