7wct
From Proteopedia
Crystal structure of FGFR4 kinase domain with 7v
Structural highlights
FunctionFGFR4_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Publication Abstract from PubMedAberrant 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 (7v) exhibited excellent potency against FGFR4, FGFR4(V550L), and FGFR4(V550M) with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound 7v demonstrated modest in vivo 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. Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.,Shao M, Chen X, Yang F, Song X, Zhou Y, Lin Q, Fu Y, Ortega R, Lin X, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2022 Mar 24;65(6):5113-5133. doi: 10.1021/acs.jmedchem.2c00096. Epub , 2022 Mar 10. PMID:35271262[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 1 reviews cite this structure No citations found See AlsoReferences
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Categories: Homo sapiens | Large Structures | Chen XJ | Chen YH | Dai SY | Lin QM
