Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTST7KB)

• DTT Name: Fibroblast growth factor receptor 3 (FGFR3)
• Synonyms: JTK4; FGFR-3; CD333
• Gene Name: FGFR3
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: FGFR3_HUMAN
• TTD ID: T91331
• EC Number: EC 2.7.10.1
• Sequence:
  MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELS
  CPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCH
  FSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAG
  NPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQT
  YTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP
  DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAE
  EELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRSPPKKGLGSPTVHKISRFPLK
  RQVSLESNASMSSNTPLVRIARLSSGEGPTLANVSELELPADPKWELSRARLTLGKPLGE
  GCFGQVVMAEAIGIDKDRAAKPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIIN
  LLGACTQGGPLYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ
  VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKKTTNGRLPVKW
  MAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCT
  HDLYMIMRECWHAAPSQRPTFKQLVEDLDRVLTVTSTDEYLDLSAPFEQYSPGGQDTPSS
  SSSGDDSVFAHDLLPPAPPSSGGSRT
• Function: 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. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  MicroRNAs in cancer (hsa05206)
  Bladder cancer (hsa05219)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway: FGFR3 mutant receptor activation (R-HSA-2033514)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pemigatinib	DM819JF	Cholangiocarcinoma	2C12.10	Approved	[2]
Trapidil	DMY67U8	Acute coronary syndrome	BA41	Phase 4	[1]

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-582664	DMDAN8H	Hepatocellular carcinoma	2C12.02	Phase 3	[3]
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]
TKI258	DMYLT67	Renal cell carcinoma	2C90	Phase 3	[3]
B-701	DMOMDA4	Bladder cancer	2C94	Phase 2	[5]
Debio 1347	DMZW50O	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
Recifercept	DML8N3Y	Achondroplasia	LD24.00	Phase 2	[7]
AEE-788	DMEOS5K	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[3]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[8]
Anti-FGFR3	DM6QENU	Multiple myeloma	2A83	Phase 1	[9]
SAR442501	DMGA3KZ	Achondroplasia	LD24.00	Phase 1	[10]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[11]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol	DMWSLTB	Discovery agent	N.A.	Investigative	[12]
ACTB-1003	DMPHSU8	Solid tumour/cancer	2A00-2F9Z	Investigative	[13]
AV-370	DMF1VS9	Solid tumour/cancer	2A00-2F9Z	Investigative	[13]
PMID21493067C1d	DMFUQIT	Discovery agent	N.A.	Investigative	[14]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[15]
SU5402	DM9JON3	Multiple myeloma	2A83	Investigative	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	5.83E-03	0.08	0.1
Renal cancer	2C82	Kidney	1.39E-06	-0.99	-2.34
Liver cancer	2C82	Liver tissue	8.57E-01	0.02	0.05
Retinoblastoma	2C82	Uvea	9.72E-06	1.46	8.79
Multiple myeloma	2C82	Bone marrow	6.39E-16	0.04	0.39

References

• [1] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] A 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.
• [4] E-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.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS One. 2020 Dec 28;15(12):e0244368.
• [8] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [9] Clinical pipeline report, company report or official report of Genentech (2011).
• [10] Clinical pipeline report, company report or official report of Sanofi
• [11] Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.
• [12] Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. J Med Chem. 2005 Oct 6;48(20):6194-201.
• [13] URL: 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).
• [14] In 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.
• [15] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.