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4XCU

Crystal Structure of FGFR4 with an Irreversible Inhibitor

Summary for 4XCU
Entry DOI10.2210/pdb4xcu/pdb
DescriptorFibroblast growth factor receptor 4, SULFATE ION, N-(2-{[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino}-3-methylphenyl)propanamide, ... (4 entities in total)
Functional Keywordsreceptor tyrosine kinase, hepatocellular carcinoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (Human)
Total number of polymer chains1
Total formula weight34474.67
Authors
Kim, J.L.,Miduturu, C.,Hodous, B.,Brooijmans, N.,Bifulco, N.,Guzi, T. (deposition date: 2014-12-18, release date: 2015-04-01, Last modification date: 2024-10-23)
Primary citationHagel, M.,Miduturu, C.,Sheets, M.,Rubin, N.,Weng, W.,Stransky, N.,Bifulco, N.,Kim, J.L.,Hodous, B.,Brooijmans, N.,Shutes, A.,Winter, C.,Lengauer, C.,Kohl, N.E.,Guzi, T.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway.
Cancer Discov, 5:424-437, 2015
Cited by
PubMed Abstract: Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC.
PubMed: 25776529
DOI: 10.1158/2159-8290.CD-14-1029
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.71 Å)
Structure validation

239492

數據於2025-07-30公開中

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