Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSAXDIL)

• DOT Name: Fibroblast growth factor receptor 3 (FGFR3)
• Synonyms: FGFR-3; EC 2.7.10.1; CD antigen CD333
• Gene Name: FGFR3
• Related Disease:
  Achondroplasia
  Camptodactyly-tall stature-scoliosis-hearing loss syndrome
  Crouzon syndrome-acanthosis nigricans syndrome
  Hypochondroplasia
  LADD syndrome 1
  Muenke syndrome
  Thanatophoric dysplasia type 1
  Thanatophoric dysplasia type 2
  Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
  LADD syndrome
  Obsolete isolated brachycephaly
  Obsolete isolated plagiocephaly
• UniProt ID: FGFR3_HUMAN
• PDB ID: 1RY7; 2LZL; 4K33; 6LVM; 6PNX; 7DHL; 7YSU
• EC Number: 2.7.10.1
• Pfam ID: PF21165 ; PF07679 ; PF13927 ; PF07714
• Sequence:
  MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELS
  CPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCH
  FSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAG
  NPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQT
  YTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP
  DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAE
  EELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRSPPKKGLGSPTVHKISRFPLK
  RQVSLESNASMSSNTPLVRIARLSSGEGPTLANVSELELPADPKWELSRARLTLGKPLGE
  GCFGQVVMAEAIGIDKDRAAKPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIIN
  LLGACTQGGPLYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ
  VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKKTTNGRLPVKW
  MAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCT
  HDLYMIMRECWHAAPSQRPTFKQLVEDLDRVLTVTSTDEYLDLSAPFEQYSPGGQDTPSS
  SSSGDDSVFAHDLLPPAPPSSGGSRT
• Function: Tyrosine-protein kinase that acts as a 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.
• Tissue Specificity: Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22-week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Endocytosis (hsa04144)
  PI3K-Akt sig.ling pathway (hsa04151)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Bladder cancer (hsa05219)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  (FGFR3)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by activated point mutants of FGFR3 (R-HSA-1839130)
  t(4 (R-HSA-2033515)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654227)
  SHC-mediated cascade (R-HSA-5654704)
  FRS-mediated FGFR3 signaling (R-HSA-5654706)
  PI-3K cascade (R-HSA-5654710)
  Negative regulation of FGFR3 signaling (R-HSA-5654732)
  Signaling by FGFR3 in disease (R-HSA-5655332)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Signaling by FGFR3 fusions in cancer (R-HSA-8853334)
  (14) translocations of FGFR3)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achondroplasia	DISYWN2O	Definitive	Autosomal dominant	[1]
Camptodactyly-tall stature-scoliosis-hearing loss syndrome	DISIVE43	Definitive	Autosomal dominant	[2]
Crouzon syndrome-acanthosis nigricans syndrome	DISR5S5K	Definitive	Autosomal dominant	[1]
Hypochondroplasia	DISHNE51	Definitive	Autosomal dominant	[1]
LADD syndrome 1	DISHGCOR	Definitive	Autosomal dominant	[3]
Muenke syndrome	DISCMUU1	Definitive	Autosomal dominant	[1]
Thanatophoric dysplasia type 1	DISLE7J4	Definitive	Autosomal dominant	[1]
Thanatophoric dysplasia type 2	DIS2RRO1	Definitive	Autosomal dominant	[1]
Severe achondroplasia-developmental delay-acanthosis nigricans syndrome	DISH38BB	Strong	Autosomal dominant	[4]
LADD syndrome	DISH8TQ5	Supportive	Autosomal dominant	[3]
Obsolete isolated brachycephaly	DIS39ZDS	Supportive	Autosomal dominant	[5]
Obsolete isolated plagiocephaly	DISSZTKC	Supportive	Autosomal dominant	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
BGJ398	DMNKBEC	Approved	Fibroblast growth factor receptor 3 (FGFR3) increases the response to substance of BGJ398.	[42]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Fibroblast growth factor receptor 3 (FGFR3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibroblast growth factor receptor 3 (FGFR3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibroblast growth factor receptor 3 (FGFR3).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Fibroblast growth factor receptor 3 (FGFR3).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Fibroblast growth factor receptor 3 (FGFR3).	[36]

34 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[21]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[22]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[23]
Thalidomide	DM70BU5	Approved	Thalidomide affects the expression of Fibroblast growth factor receptor 3 (FGFR3).	[24]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[25]
Pomalidomide	DMTGBAX	Approved	Pomalidomide affects the expression of Fibroblast growth factor receptor 3 (FGFR3).	[24]
Lenalidomide	DM6Q7U4	Approved	Lenalidomide decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[24]
Midostaurin	DMI6E0R	Approved	Midostaurin decreases the activity of Fibroblast growth factor receptor 3 (FGFR3).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[19]
Masitinib	DMRSNEU	Phase 3	Masitinib decreases the activity of Fibroblast growth factor receptor 3 (FGFR3).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[29]
Gossypol	DMJWE3I	Phase 2	Gossypol decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[33]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Fibroblast growth factor receptor 3 (FGFR3).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[37]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[38]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[39]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Fibroblast growth factor receptor 3 (FGFR3).	[40]
PD173074	DMP0N4U	Investigative	PD173074 decreases the activity of Fibroblast growth factor receptor 3 (FGFR3).	[41]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Fibroblast growth factor receptor 3 (FGFR3).	[30]

References

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