Target Information
Target General Information | Top | |||||
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Target ID |
T41515
(Former ID: TTDR01438)
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Target Name |
FGFR4 messenger RNA (FGFR4 mRNA)
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Synonyms |
TKF (mRNA); JTK2 (mRNA); FGFR-4 (mRNA); CD334 (mRNA)
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Gene Name |
FGFR4
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Obesity [ICD-11: 5B80-5B81] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
3 | Liver cancer [ICD-11: 2C12] | |||||
Function |
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. 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.
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BioChemical Class |
mRNA target
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UniProt ID | ||||||
EC Number |
EC 2.7.10.1
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Sequence |
MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRA
ERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDS LTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTP TIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLD VLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFP YVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA AAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSL ESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQ VVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVC TQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGM QYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEA LFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYG LMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDS VFSHDPLPLGSSSFPFGSGVQT Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | ISIS-FGFR4 | Drug Info | Phase 2 | Obesity | [2] | |
2 | FGF401 | Drug Info | Phase 1/2 | Hepatocellular carcinoma | [1] | |
3 | BLU-554 | Drug Info | Phase 1 | Hepatocellular carcinoma | [1] | |
4 | H3B-6527 | Drug Info | Phase 1 | Hepatocellular carcinoma | [1] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | PD-0183812 | Drug Info | Terminated | Retinoblastoma | [3] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Antagonist | [+] 1 Antagonist drugs | + | ||||
1 | FGF401 | Drug Info | [1] | |||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | BLU-554 | Drug Info | [1], [5] | |||
2 | H3B-6527 | Drug Info | [1] | |||
3 | PD-0183812 | Drug Info | [6] | |||
4 | Ro-4396686 | Drug Info | [7] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 7 KEGG Pathways | + | ||||
1 | MAPK signaling pathway | |||||
2 | Ras signaling pathway | |||||
3 | Rap1 signaling pathway | |||||
4 | Endocytosis | |||||
5 | PI3K-Akt signaling pathway | |||||
6 | Signaling pathways regulating pluripotency of stem cells | |||||
7 | Regulation of actin cytoskeleton | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | FGF signaling pathway | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | FGF signaling pathway | |||||
Reactome | [+] 10 Reactome Pathways | + | ||||
1 | PI3K Cascade | |||||
2 | PIP3 activates AKT signaling | |||||
3 | FGFR4 ligand binding and activation | |||||
4 | Constitutive Signaling by Aberrant PI3K in Cancer | |||||
5 | Phospholipase C-mediated cascade | |||||
6 | FRS-mediated FGFR4 signaling | |||||
7 | SHC-mediated cascade:FGFR4 | |||||
8 | PI-3K cascade:FGFR4 | |||||
9 | Negative regulation of FGFR4 signaling | |||||
10 | RAF/MAP kinase cascade | |||||
WikiPathways | [+] 4 WikiPathways | + | ||||
1 | Regulation of Actin Cytoskeleton | |||||
2 | Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) | |||||
3 | PIP3 activates AKT signaling | |||||
4 | Signaling by FGFR |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | ClinicalTrials.gov (NCT02476019) A Safety, Tolerability, PK, and PD Study of Once Weekly ISIS-FGFR4RX SC in Obese Patients. | |||||
REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014130) | |||||
REF 4 | Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011). | |||||
REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 6 | Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16. | |||||
REF 7 | Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. |
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