8XLO

FGFR1 kinase domain with a dual-warhead covalent inhibitor CXF-007

これはPDB形式変換不可エントリーです。

8XLO の概要

• エントリーDOI: 10.2210/pdb8xlo/pdb
• 分子名称: Fibroblast growth factor receptor 1, CXF007, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: fibroblast growth factor receptor 1, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72344.76

構造登録者

Chen, X.J.,Chen, Y.H. (登録日: 2023-12-26, 公開日: 2024-03-27, 最終更新日: 2024-11-13)

主引用文献

Chen, X.,Li, H.,Lin, Q.,Dai, S.,Qu, L.,Guo, M.,Zhang, L.,Liao, J.,Wei, H.,Xu, G.,Jiang, L.,Chen, Y.
Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4.
Eur.J.Med.Chem., 268:116281-116281, 2024

PubMed Abstract: Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.

PubMed: 38432058
DOI: 10.1016/j.ejmech.2024.116281

実験手法

X-RAY DIFFRACTION (2.36 Å)