4XCU

Crystal Structure of FGFR4 with an Irreversible Inhibitor

4XCU の概要

• エントリーDOI: 10.2210/pdb4xcu/pdb
• 分子名称: Fibroblast 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)
• 機能のキーワード: receptor tyrosine kinase, hepatocellular carcinoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34474.67

構造登録者

Kim, J.L.,Miduturu, C.,Hodous, B.,Brooijmans, N.,Bifulco, N.,Guzi, T. (登録日: 2014-12-18, 公開日: 2015-04-01, 最終更新日: 2024-10-23)

主引用文献

Hagel, 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

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

実験手法

X-RAY DIFFRACTION (1.71 Å)