Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1VAUK)

• DTT Name: VEGFR1 messenger RNA (VEGFR1 mRNA)
• Synonyms: Vascular permeability factor receptor (mRNA); VEGFR1 (mRNA); VEGFR-1 (mRNA); VEGF-1 receptor (mRNA); Tyrosine-protein kinase receptor FLT (mRNA); Tyrosine-protein kinase FRT (mRNA); Fms-like tyrosine kinase 1 (mRNA); FRT (mRNA); FLT (mRNA)
• Gene Name: FLT1
• DTT Type: Successful target; [1]
• BioChemical Class: mRNA target
• UniProt ID: VGFR1_HUMAN
• TTD ID: T80782
• EC Number: EC 2.7.10.1
• 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: 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. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. 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. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. 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.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  HIF-1 signaling pathway (hsa04066)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Transcriptional 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 DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
VATALANIB	DMY0UEQ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[3]
Sirna-027	DMZTQD8	Exudative age-related macular degeneration	9B78.3Z	Phase 1/2	[4]

31 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2-Methoxy-phenyl)-(5-phenyl-oxazol-2-yl)-amine	DMQWD75	Discovery agent	N.A.	Investigative	[5]
(5-Phenyl-oxazol-2-yl)-m-tolyl-amine	DM1R5SF	Discovery agent	N.A.	Investigative	[5]
2-(1H-indazol-3-yl)-1H-benzo[d]imidazole	DM0CSH8	Discovery agent	N.A.	Investigative	[6]
2-(5-Phenyl-oxazol-2-ylamino)-benzonitrile	DMX6QMT	Discovery agent	N.A.	Investigative	[5]
3,6-Di-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine	DMNV0EZ	Discovery agent	N.A.	Investigative	[7]
3-(5-Phenyl-oxazol-2-ylamino)-benzonitrile	DMPBLM2	Discovery agent	N.A.	Investigative	[5]
4-(5-Phenyl-oxazol-2-ylamino)-benzenesulfonamide	DM3N9O5	Discovery agent	N.A.	Investigative	[5]
4-(isoquinolin-5-yl)-N-m-tolylphthalazin-1-amine	DM8LODU	Discovery agent	N.A.	Investigative	[8]
4-(isoquinolin-5-yl)-N-o-tolylphthalazin-1-amine	DMS30HQ	Discovery agent	N.A.	Investigative	[8]
4-Chloro-N-(2-chloro-benzoyl)-benzenesulfonamide	DMVJ61A	Discovery agent	N.A.	Investigative	[9]
4-Chloro-N-(2-methyl-benzoyl)-benzenesulfonamide	DM6SI78	Discovery agent	N.A.	Investigative	[9]
4-Chloro-N-(3-chloro-benzoyl)-benzenesulfonamide	DMI3OR9	Discovery agent	N.A.	Investigative	[9]
4-Chloro-N-(4-chloro-benzoyl)-benzenesulfonamide	DMTDX2S	Discovery agent	N.A.	Investigative	[9]
4-Chloro-N-(4-nitro-benzoyl)-benzenesulfonamide	DMM0TL6	Discovery agent	N.A.	Investigative	[9]
AAL-993	DM35RFH	Discovery agent	N.A.	Investigative	[2]
CB-676475	DMXON4L	Discovery agent	N.A.	Investigative	[10]
Cdk1/2 inhibitor III	DMS62T0	Discovery agent	N.A.	Investigative	[11]
C[homoPhe-Hca-Glu-Gly-Leu-Glu-Glu]-NH2	DM8HK0J	Discovery agent	N.A.	Investigative	[12]
C[YYAEGLEE]-NH2	DM0YLPV	Discovery agent	N.A.	Investigative	[13]
C[YYDEGLEE]-NH2	DMSKW8H	Discovery agent	N.A.	Investigative	[13]
C[YYDEKLEE]-NH2	DMTHGMR	Discovery agent	N.A.	Investigative	[13]
IM-094261	DMTFV65	Discovery agent	N.A.	Investigative	[14]
IM-094882	DMO18YN	Discovery agent	N.A.	Investigative	[8]
LYCOGARUBIN B	DMVX19Q	Discovery agent	N.A.	Investigative	[15]
N-(2,4-Dichloro-benzoyl)-benzenesulfonamide	DMHI4Y6	Discovery agent	N.A.	Investigative	[9]
N-(3-Bromo-benzoyl)-4-chloro-benzenesulfonamide	DMOQ08F	Discovery agent	N.A.	Investigative	[9]
N3-GHQMFYYPra-NH2	DMQEGJU	Discovery agent	N.A.	Investigative	[16]
Phenyl-(5-phenyl-oxazol-2-yl)-amine	DMR2B4O	Discovery agent	N.A.	Investigative	[5]
PMID17935989C25	DML8ZBR	Discovery agent	N.A.	Investigative	[17]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[18]
[3-(5-Phenyl-oxazol-2-ylamino)-phenyl]-methanol	DMD0LCU	Discovery agent	N.A.	Investigative	[5]

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	1.64E-05	0.29	0.51
Myelodysplastic syndrome	2C82	Bone marrow	2.87E-04	0.2	0.92
Rectal cancer	2C82	Rectal colon tissue	6.82E-03	0.54	1.33
Thyroid cancer	2C82	Thyroid	1.01E-08	0.46	1.04
Liver cancer	2C82	Liver tissue	2.75E-04	0.63	0.78
Renal cancer	2C82	Kidney	3.48E-03	0.9	1.6
Lung cancer	2C82	Lung tissue	2.04E-09	-0.08	-0.13
Breast cancer	2C82	Breast tissue	5.78E-01	-0.11	-0.15
Acute myelocytic leukaemia	2C82	Bone marrow	7.84E-01	-0.01	-0.06
Head and neck cancer	2C82	Head and neck tissue	1.96E-20	1.1	1.4

References

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• [4] 2011 Pipeline of Sirna Therapeutics.
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