8KH8
Crystal structure of FGFR4(V550L) kinase domain with 8z
Summary for 8KH8
| Entry DOI | 10.2210/pdb8kh8/pdb |
| Descriptor | Fibroblast growth factor receptor 4, SULFATE ION, 1-[4-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-3-[6-methanoyl-5-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3-(2-morpholin-4-ylethoxy)pyridin-2-yl]urea, ... (5 entities in total) |
| Functional Keywords | fgfr4 kinase domain, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35393.57 |
| Authors | Lin, Q.M.,Chen, X.J.,Chen, Y.H. (deposition date: 2023-08-21, release date: 2024-07-31, Last modification date: 2024-11-20) |
| Primary citation | Yang, F.,Lin, Q.,Song, X.,Huang, H.,Chen, X.,Tan, J.,Li, Y.,Zhou, Y.,Tu, Z.,Du, H.,Zhang, Z.M.,Ortega, R.,Lin, X.,Patterson, A.V.,Smaill, J.B.,Chen, Y.,Lu, X. Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity. J.Med.Chem., 67:2667-2689, 2024 Cited by PubMed Abstract: Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea exhibited excellent potency against FGFR4, FGFR4, and FGFR4 with IC values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4, FGFR4, and FGFR4, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients. PubMed: 38348819DOI: 10.1021/acs.jmedchem.3c01810 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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