Details of Drug Off-Target (DOT)

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

• DOT Name: Fibroblast growth factor receptor 2 (FGFR2)
• Synonyms: FGFR-2; EC 2.7.10.1; K-sam; KGFR; Keratinocyte growth factor receptor; CD antigen CD332
• Gene Name: FGFR2
• Related Disease:
  Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
  Apert syndrome
  Beare-Stevenson cutis gyrata syndrome
  Crouzon syndrome
  Jackson-Weiss syndrome
  LADD syndrome 1
  Pfeiffer syndrome
  Bent bone dysplasia syndrome 1
  Familial scaphocephaly syndrome, McGillivray type
  Saethre-Chotzen syndrome
  Antley-Bixler syndrome
  LADD syndrome
  Pfeiffer syndrome type 1
  Pfeiffer syndrome type 2
  Pfeiffer syndrome type 3
• UniProt ID: FGFR2_HUMAN
• PDB ID: 1DJS ; 1E0O ; 1EV2 ; 1GJO ; 1II4 ; 1IIL ; 1NUN ; 1OEC ; 1WVZ ; 2FDB ; 2PSQ ; 2PVF ; 2PVY ; 2PWL ; 2PY3 ; 2PZ5 ; 2PZP ; 2PZR ; 2Q0B ; 3B2T ; 3CAF ; 3CLY ; 3CU1 ; 3DAR ; 3EUU ; 3OJ2 ; 3OJM ; 3RI1 ; 4J23 ; 4J95 ; 4J96 ; 4J97 ; 4J98 ; 4J99 ; 4WV1 ; 5EG3 ; 5UGL ; 5UGX ; 5UHN ; 5UI0 ; 6AGX ; 6LVK ; 6LVL ; 6V6Q ; 7KIA ; 7KIE ; 7OZY ; 8E1X ; 8H75 ; 8STG
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF13927 ; PF07714
• Sequence:
  MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEV
  RCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYF
  MVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCP
  AGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSI
  NHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSK
  YGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVL
  PAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVILCRMKNTTKKPDFSSQPAVHKLTK
  RIPLRRQVTVSAESSSSMNSNTPLVRITTRLSSTADTPMLAGVSEYELPEDPKWEFPRDK
  LTLGKPLGEGCFGQVVMAEAVGIDKDKPKEAVTVAVKMLKDDATEKDLSDLVSEMEMMKM
  IGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLRARRPPGMEYSYDINRVPEEQMTF
  KDLVSCTYQLARGMEYLASQKCIHRDLAARNVLVTENNVMKIADFGLARDINNIDYYKKT
  TNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLMWEIFTLGGSPYPGIPVEELFKLLKEGH
  RMDKPANCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRILTLTTNEEYLDLSQPLEQYS
  PSYPDTRSSCSSGDDSVFSPDPMPYEPCLPQYPHINGSVKT
• 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, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. 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. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1.
• 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)
  Prostate cancer (hsa05215)
  Gastric cancer (hsa05226)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  (FGFR2)
  PIP3 activates AKT signaling (R-HSA-1257604)
  FGFR2c ligand binding and activation (R-HSA-190375)
  FGFR2b ligand binding and activation (R-HSA-190377)
  Signaling by FGFR2 amplification mutants (R-HSA-2023837)
  Activated point mutants of FGFR2 (R-HSA-2033519)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654221)
  PI-3K cascade (R-HSA-5654695)
  SHC-mediated cascade (R-HSA-5654699)
  FRS-mediated FGFR2 signaling (R-HSA-5654700)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Signaling by FGFR2 in disease (R-HSA-5655253)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Signaling by FGFR2 IIIa TM (R-HSA-8851708)
  Signaling by FGFR2 fusions (R-HSA-8853333)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis	DISXGAEX	Definitive	Autosomal dominant	[1]
Apert syndrome	DISGIYXQ	Definitive	Autosomal dominant	[2]
Beare-Stevenson cutis gyrata syndrome	DISS2MSO	Definitive	Autosomal dominant	[2]
Crouzon syndrome	DISIAVZU	Definitive	Autosomal dominant	[2]
Jackson-Weiss syndrome	DISRNZHH	Definitive	Autosomal dominant	[3]
LADD syndrome 1	DISHGCOR	Definitive	Autosomal dominant	[1]
Pfeiffer syndrome	DISA0GA5	Definitive	Autosomal dominant	[2]
Bent bone dysplasia syndrome 1	DISP6GAO	Strong	Autosomal dominant	[4]
Familial scaphocephaly syndrome, McGillivray type	DISKLE9L	Strong	Autosomal dominant	[5]
Saethre-Chotzen syndrome	DIS3A437	Strong	Autosomal dominant	[5]
Antley-Bixler syndrome	DISH25CS	Supportive	Autosomal dominant	[6]
LADD syndrome	DISH8TQ5	Supportive	Autosomal dominant	[7]
Pfeiffer syndrome type 1	DISA0WVT	Supportive	Autosomal dominant	[8]
Pfeiffer syndrome type 2	DISI9RUN	Supportive	Autosomal dominant	[8]
Pfeiffer syndrome type 3	DISK68G7	Supportive	Autosomal dominant	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Fibroblast growth factor receptor 2 (FGFR2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Fibroblast growth factor receptor 2 (FGFR2).	[17]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[20]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[21]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[22]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[23]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[24]
Diazepam	DM08E9O	Approved	Diazepam decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[25]
Lenalidomide	DM6Q7U4	Approved	Lenalidomide decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[26]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[15]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Fibroblast growth factor receptor 2 (FGFR2).	[30]
T83193	DMHO29Y	Patented	T83193 decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[31]
HSDB-41	DMR8VJA	Preclinical	HSDB-41 increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Fibroblast growth factor receptor 2 (FGFR2).	[32]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[31]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[33]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Fibroblast growth factor receptor 2 (FGFR2).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Fibroblast growth factor receptor 2 (FGFR2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibroblast growth factor receptor 2 (FGFR2).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sucrose Octasulfate	DMET64R	Investigative	Sucrose Octasulfate affects the binding of Fibroblast growth factor receptor 2 (FGFR2).	[35]

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