7WCW

Crystal structure of FGFR4(V550L) kinase domain with 7v

Summary for 7WCW

• Entry DOI: 10.2210/pdb7wcw/pdb
• Descriptor: Fibroblast growth factor receptor 4, ~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, structural protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35467.62

Authors

Chen, X.J.,Lin, Q.M.,Dai, S.Y.,Chen, Y.H. (deposition date: 2021-12-20, release date: 2022-03-30, Last modification date: 2023-11-29)

Primary citation

Shao, M.,Chen, X.,Yang, F.,Song, X.,Zhou, Y.,Lin, Q.,Fu, Y.,Ortega, R.,Lin, X.,Tu, Z.,Patterson, A.V.,Smaill, J.B.,Chen, Y.,Lu, X.
Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.
J.Med.Chem., 65:5113-5133, 2022

PubMed Abstract: Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound () exhibited excellent potency against FGFR4, FGFR4, and FGFR4 with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound demonstrated modest antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.

PubMed: 35271262
DOI: 10.1021/acs.jmedchem.2c00096

Experimental method

X-RAY DIFFRACTION (2.317 Å)