| Structural highlights
Function
FGFR4_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 PubMed
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-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4(WT), FGFR4(V550L), and FGFR4(V550M) with IC(50) values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4(WT), FGFR4(V550L), and FGFR4(V550M), and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC(50) values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z 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.
Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.,Yang F, Lin Q, Song X, Huang H, Chen X, Tan J, Li Y, Zhou Y, Tu Z, Du H, Zhang ZM, Ortega R, Lin X, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2024 Feb 22;67(4):2667-2689. doi: 10.1021/acs.jmedchem.3c01810. Epub , 2024 Feb 13. PMID:38348819[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Vainikka S, Joukov V, Wennstrom S, Bergman M, Pelicci PG, Alitalo K. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem. 1994 Jul 15;269(28):18320-6. PMID:7518429
- ↑ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996 Jun 21;271(25):15292-7. PMID:8663044
- ↑ Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol. 2001 Jul;3(7):650-7. PMID:11433297 doi:http://dx.doi.org/10.1038/35083041
- ↑ Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9;281(23):15694-700. Epub 2006 Apr 4. PMID:16597617 doi:10.1074/jbc.M601252200
- ↑ Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007 Sep 14;282(37):26687-95. Epub 2007 Jul 10. PMID:17623664 doi:10.1074/jbc.M704165200
- ↑ Citores L, Bai L, Sorensen V, Olsnes S. Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus. J Cell Physiol. 2007 Jul;212(1):148-56. PMID:17311277 doi:10.1002/jcp.21014
- ↑ Haugsten EM, Malecki J, Bjorklund SM, Olsnes S, Wesche J. Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis. Mol Biol Cell. 2008 Aug;19(8):3390-403. doi: 10.1091/mbc.E07-12-1219. Epub 2008, May 14. PMID:18480409 doi:10.1091/mbc.E07-12-1219
- ↑ Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008 Aug;10(8):847-56. PMID:18670643
- ↑ Triantis V, Saeland E, Bijl N, Oude-Elferink RP, Jansen PL. Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19-mediated down-regulation of cytochrome P450 7A1. Hepatology. 2010 Aug;52(2):656-66. doi: 10.1002/hep.23708. PMID:20683963 doi:http://dx.doi.org/10.1002/hep.23708
- ↑ Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, Hager T, Wang Z, Lindberg R, Li Y. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010 Feb 19;285(8):5165-70. doi: 10.1074/jbc.M109.068783. Epub 2009 , Dec 15. PMID:20018895 doi:http://dx.doi.org/10.1074/jbc.M109.068783
- ↑ Sugiyama N, Varjosalo M, Meller P, Lohi J, Chan KM, Zhou Z, Alitalo K, Taipale J, Keski-Oja J, Lehti K. FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15786-91. doi:, 10.1073/pnas.0914459107. Epub 2010 Aug 23. PMID:20798051 doi:http://dx.doi.org/10.1073/pnas.0914459107
- ↑ Nakamura M, Uehara Y, Asada M, Honda E, Nagai N, Kimata K, Suzuki M, Imamura T. Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho. J Biol Chem. 2011 Jul 29;286(30):26418-23. doi: 10.1074/jbc.M111.251140. Epub, 2011 Jun 8. PMID:21653700 doi:http://dx.doi.org/10.1074/jbc.M111.251140
- ↑ Sugiyama N, Varjosalo M, Meller P, Lohi J, Hyytiainen M, Kilpinen S, Kallioniemi O, Ingvarsen S, Engelholm LH, Taipale J, Alitalo K, Keski-Oja J, Lehti K. Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation. Cancer Res. 2010 Oct 15;70(20):7851-61. doi: 10.1158/0008-5472.CAN-10-1223. Epub , 2010 Sep 28. PMID:20876804 doi:http://dx.doi.org/10.1158/0008-5472.CAN-10-1223
- ↑ Yang F, Lin Q, Song X, Huang H, Chen X, Tan J, Li Y, Zhou Y, Tu Z, Du H, Zhang ZM, Ortega R, Lin X, Patterson AV, Smaill JB, 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. 2024 Feb 22;67(4):2667-2689. PMID:38348819 doi:10.1021/acs.jmedchem.3c01810
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