Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT0OGYS)

• DOT Name: Vascular endothelial growth factor receptor 1 (FLT1)
• Synonyms: VEGFR-1; EC 2.7.10.1; Fms-like tyrosine kinase 1; FLT-1; Tyrosine-protein kinase FRT; Tyrosine-protein kinase receptor FLT; FLT; Vascular permeability factor receptor
• Gene Name: FLT1
• UniProt ID: VGFR1_HUMAN
• PDB ID: 1FLT; 1QSV; 1QSZ; 1QTY; 1RV6; 2XAC; 3HNG; 4CKV; 4CL7; 5ABD; 5EX3; 5T89
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF00047 ; PF13927 ; PF07714 ; PF21339 ; PF17988
• Sequence:
  MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHK
  WSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKET
  ESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPD
  GKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPV
  KLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDK
  MQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVK
  AFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTA
  TLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARC
  DFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNK
  VGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTM
  HYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIRDQEA
  PYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIILGPGSSTLFIER
  VTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLELITLTCTCVAATLFWLLLTLFI
  RKMKRSSSEIKTDYLSIIMDPDEVPLDEQCERLPYDASKWEFARERLKLGKSLGRGAFGK
  VVQASAFGIKKSPTCRTVAVKMLKEGATASEYKALMTELKILTHIGHHLNVVNLLGACTK
  QGGPLMVIVEYCKYGNLSNYLKSKRDLFFLNKDAALHMEPKKEKMEPGLEQGKKPRLDSV
  TSSESFASSGFQEDKSLSDVEEEEDSDGFYKEPITMEDLISYSFQVARGMEFLSSRKCIH
  RDLAARNILLSENNVVKICDFGLARDIYKNPDYVRKGDTRLPLKWMAPESIFDKIYSTKS
  DVWSYGVLLWEIFSLGGSPYPGVQMDEDFCSRLREGMRMRAPEYSTPEIYQIMLDCWHRD
  PKERPRFAELVEKLGDLLQANVQQDGKDYIPINAILTGNSGFTYSTPAFSEDFFKESISA
  PKFNSGSSDDVRYVNAFKFMSLERIKTFEELLPNATSMFDDYQGDSSTLLASPMLKRFTW
  TDSKPKASLKIDLRVTSKSKESGLSDVSRPSFCHSSCGHVSEGKRRFTYDHAELERKIAC
  CSPPPDYNSVVLYSTPPI
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 ; [Isoform 1]: Phosphorylates PLCG; [Isoform 2]: May function as decoy receptor for VEGFA; [Isoform 3]: May function as decoy receptor for VEGFA; [Isoform 4]: May function as decoy receptor for VEGFA; [Isoform 7]: Has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.
• Tissue Specificity: Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC).
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  HIF-1 sig.ling pathway (hsa04066)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Transcriptio.l misregulation in cancer (hsa05202)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  VEGF binds to VEGFR leading to receptor dimerization (R-HSA-195399)
  Neurophilin interactions with VEGF and VEGFR (R-HSA-194306)

Molecular Interaction Atlas (MIA) of This DOT

2 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 Vascular endothelial growth factor receptor 1 (FLT1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Vascular endothelial growth factor receptor 1 (FLT1).	[24]

37 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 Vascular endothelial growth factor receptor 1 (FLT1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[14]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[15]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[15]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[18]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[10]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[20]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[21]
MK-2206	DMT1OZ6	Phase 2	MK-2206 decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[22]
MK-2461	DM21WBH	Phase 1/2	MK-2461 decreases the activity of Vascular endothelial growth factor receptor 1 (FLT1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[25]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Vascular endothelial growth factor receptor 1 (FLT1).	[26]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[30]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[31]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[32]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[33]
Fascaplysin	DMG5OZP	Investigative	Fascaplysin decreases the expression of Vascular endothelial growth factor receptor 1 (FLT1).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the secretion of Vascular endothelial growth factor receptor 1 (FLT1).	[7]

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