Target General Infomation
Target ID
T91331
Former ID
TTDC00131
Target Name
FGF-3 receptor
Gene Name
FGFR3
Synonyms
FGFR-3; CD333; Fibroblast growth factor receptor 3; FGFR3
Target Type
Clinical Trial
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Advanced or metastatic renal cell cancer [ICD9: 189; ICD10: C64]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hepatocellular carcinoma [ICD9: 155; ICD10: C22.0]
Multiple myeloma [ICD9: 203; ICD10: C90]
Retinoblastoma [ICD10: C69.2]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL 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. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling.
BioChemical Class
Kinase
Target Validation
T91331
UniProt ID
EC Number
EC 2.7.10.1
Sequence
MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELS
CPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCH
FSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAG
NPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQT
YTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP
DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAE
EELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRSPPKKGLGSPTVHKISRFPLK
RQVSLESNASMSSNTPLVRIARLSSGEGPTLANVSELELPADPKWELSRARLTLGKPLGE
GCFGQVVMAEAIGIDKDRAAKPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIIN
LLGACTQGGPLYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ
VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKKTTNGRLPVKW
MAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCT
HDLYMIMRECWHAAPSQRPTFKQLVEDLDRVLTVTSTDEYLDLSAPFEQYSPGGQDTPSS
SSSGDDSVFAHDLLPPAPPSSGGSRT
Structure
1RY7; 2LZL; 4K33
Drugs and Mode of Action
Drug(s) BMS-582664 Drug Info Phase 3 Hepatocellular carcinoma [522676], [542969]
E-3810 Drug Info Phase 3 Solid tumours [524749], [542632]
AEE-788 Drug Info Phase 1/2 Solid tumours [521635], [542626]
MK-2461 Drug Info Phase 1/2 Alzheimer disease [530708]
TKI258 Drug Info Phase 1/2 Advanced or metastatic renal cell cancer [536674], [541242]
Anti-FGFR3 Drug Info Phase 1 Multiple myeloma [550794]
PD-0183812 Drug Info Terminated Retinoblastoma [547217]
Inhibitor 5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol Drug Info [527769]
ACTB-1003 Drug Info [543497]
AEE-788 Drug Info [536474]
BMS-582664 Drug Info [536474]
compound 1d Drug Info [531435]
E-3810 Drug Info [525382]
MK-2461 Drug Info [530708]
PD-0183812 Drug Info [525924]
Ro-4396686 Drug Info [528018]
SU10991 Drug Info [537114]
SU5402 Drug Info [537114]
TKI258 Drug Info [536474]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway MAPK signaling pathway
Ras signaling pathway
Rap1 signaling pathway
Endocytosis
PI3K-Akt signaling pathway
Signaling pathways regulating pluripotency of stem cells
Regulation of actin cytoskeleton
Pathways in cancer
MicroRNAs in cancer
Bladder cancer
Central carbon metabolism in cancer
PANTHER Pathway FGF signaling pathway
Reactome FGFR3 mutant receptor activation
WikiPathways Regulation of Actin Cytoskeleton
Endochondral Ossification
Bladder Cancer
Neural Crest Differentiation
Signaling by FGFR
References
Ref 521635ClinicalTrials.gov (NCT00107237) AEE788 and Everolimus in Treating Patients With Recurrent or Relapsed Glioblastoma Multiforme. U.S. National Institutes of Health.
Ref 522676ClinicalTrials.gov (NCT00908752) Phase III Trans-Arterial Chemo-Embolization (TACE) Adjuvant HCC. U.S. National Institutes of Health.
Ref 524749ClinicalTrials.gov (NCT02135107) A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients. U.S. National Institutes of Health.
Ref 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 536674A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2008 Apr 1;14(7):2075-81.
Ref 541242(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5962).
Ref 542626(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7643).
Ref 542632(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7649).
Ref 542969(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8097).
Ref 547217Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014130)
Ref 550794Clinical pipeline report, company report or official report of Genentech (2011).
Ref 525382E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405. doi: 10.1158/0008-5472.CAN-10-2700. Epub 2011 Jan 6.
Ref 525924J Med Chem. 2000 Nov 30;43(24):4606-16.Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.
Ref 527769J Med Chem. 2005 Oct 6;48(20):6194-201.Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases.
Ref 528018Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. Epub 2006 Feb 3.Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis.
Ref 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 531435In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61.
Ref 536474A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 543497(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1810).
Ref 550794Clinical pipeline report, company report or official report of Genentech (2011).

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