8XLO
FGFR1 kinase domain with a dual-warhead covalent inhibitor CXF-007
This is a non-PDB format compatible entry.
Summary for 8XLO
| Entry DOI | 10.2210/pdb8xlo/pdb |
| Descriptor | Fibroblast growth factor receptor 1, CXF007, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | fibroblast growth factor receptor 1, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 72344.76 |
| Authors | Chen, X.J.,Chen, Y.H. (deposition date: 2023-12-26, release date: 2024-03-27, Last modification date: 2024-11-13) |
| Primary citation | 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 Cited by 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: 38432058DOI: 10.1016/j.ejmech.2024.116281 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.36 Å) |
Structure validation
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