7V29

Crystal structure of FGFR4 with a dual-warhead covalent inhhibitor

Summary for 7V29

• Entry DOI: 10.2210/pdb7v29/pdb
• Descriptor: Fibroblast growth factor receptor 4, N-[2-[[3-(3,5-dimethoxyphenyl)-2-oxidanylidene-1-[3-(4-propanoylpiperazin-1-yl)propyl]-4H-pyrimido[4,5-d]pyrimidin-7-yl]amino]phenyl]propanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, dual-warhead, fibroblast growth factor receptor 4, covalent, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71131.91

Authors

Chen, X.J.,Jiang, L.Y.,Dai, S.Y.,Qu, L.Z.,Chen, Y.H. (deposition date: 2021-08-07, release date: 2022-03-30, Last modification date: 2024-10-09)

Primary citation

Chen, X.,Li, H.,Lin, Q.,Dai, S.,Yue, S.,Qu, L.,Li, M.,Guo, M.,Wei, H.,Li, J.,Jiang, L.,Xu, G.,Chen, Y.
Structure-based design of a dual-warhead covalent inhibitor of FGFR4.
Commun Chem, 5:36-36, 2022

PubMed Abstract: The fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.

PubMed: 36697897
DOI: 10.1038/s42004-022-00657-9

Experimental method

X-RAY DIFFRACTION (1.983 Å)