Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2Q6G1)

• DTT Name: Vascular endothelial growth factor receptor 1 (FLT-1)
• Synonyms: Vascular permeability factor receptor; VEGFR1; VEGFR-1; VEGF-1 receptor; Tyrosine-protein kinase receptor FLT; Tyrosine-protein kinase FRT; Fms-like tyrosine kinase 1; FRT; FLT
• Gene Name: FLT1
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: VGFR1_HUMAN
• TTD ID: T63966
• 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

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fruquintinib	DMHOSCQ	Colorectal cancer	2B91.Z	Approved	[2]
Tivozanib	DMUKC5L	Renal cell carcinoma	2C90	Approved	[3]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]
Sulfatinib	DMPOTM4	Neuroendocrine cancer	2B72.1	Phase 3	[5]
Famitinib	DMSFWT7	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
LY3012212	DMRVEHY	Arteriosclerosis	BD40	Phase 2	[7]
OCV-101	DMT9QI2	Pancreatic cancer	2C10	Phase 2	[8]
X-82	DMW1NKO	Age-related macular degeneration	9B75.0	Phase 2	[9]
OTSGC-A24	DMN0ZQ5	Colorectal cancer	2B91.Z	Phase 1/2	[10]
CEP-11981	DMYDTJ6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
EW-A-401	DM3VC6T	Peripheral vascular disease	BD4Z	Phase 1	[12]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Angiozyme	DMBQLS5	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[13]
Telbermin	DMIDGZU	Diabetic foot ulcer	BD54	Discontinued in Phase 2	[14]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AAL-993	DM35RFH	Discovery agent	N.A.	Investigative	[15]
SU-11652	DMGQXN7	Discovery agent	N.A.	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Ovarian cancer	2C82	Ovarian tissue	4.94E-03	0.74	1.24
Renal cancer	2C82	Kidney	3.48E-03	0.9	1.6
Bladder cancer	2C82	Bladder tissue	1.30E-04	0.79	2.48
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
Liver cancer	2C82	Liver tissue	2.75E-04	0.63	0.78
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

• [1] Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006 Oct;26(8):859-70.
• [2] Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
• [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 Hutchison Medi Pharma.
• [6] Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
• [7] Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study. Invest New Drugs. 2014 Apr;32(2):303-11.
• [8] Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor.Cancer Sci.2013 Jan;104(1):98-104.
• [9] National Cancer Institute Drug Dictionary (drug id 695817).
• [10] J Clin Oncol 33, 2015 (suppl 3; abstr 65).
• [11] 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. (Ligand id: 8189).
• [12] DOI: http://dx.doi.org/10.1016/j.tips.2014.09.007
• [13] An open-label, phase 2 trial of RPI.4610 (Angiozyme) in the treatment of metastatic breast cancer.Cancer.2012 Sep 1;118(17):4098-104.
• [14] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [15] Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem. 2002 Dec 19;45(26):5687-93.
• [16] Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel... J Med Chem. 2003 Mar 27;46(7):1116-9.