Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTDCBX5)

• DTT Name: Vascular endothelial growth factor receptor 3 (FLT-4)
• Synonyms: VEGFR3; VEGFR-3; VEGF-3 receptor; Tyrosine-protein kinase receptor FLT4; Fms-like tyrosine kinase 4
• Gene Name: FLT4
• DTT Type: Successful target; [1]
• Related Disease: Renal cell carcinoma [ICD-11: 2C90]
• BioChemical Class: Kinase
• UniProt ID: VGFR3_HUMAN
• TTD ID: T07303
• EC Number: EC 2.7.10.1
• Sequence:
  MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWA
  WPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARI
  EGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDG
  QEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSL
  ELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNV
  SQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAA
  YPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNV
  PPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQ
  DLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKV
  GQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHD
  AHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRS
  HDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEE
  KSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILV
  GTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEF
  PRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKIL
  IHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRF
  RAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQ
  VARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKW
  MAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELA
  TPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFS
  QVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPM
  TPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRR
  RPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY
• Function: Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'. Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt signaling pathway (hsa04151)
  Focal adhesion (hsa04510)
• Reactome Pathway: VEGF binds to VEGFR leading to receptor dimerization (R-HSA-195399)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tivozanib	DMUKC5L	Renal cell carcinoma	2C90	Approved	[2]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-869	DMREDYP	Solid tumour/cancer	2A00-2F9Z	Phase 3	[3], [4]
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]
Fruquintinib	DMHOSCQ	Solid tumour/cancer	2A00-2F9Z	Phase 3	[6]
PI-88	DMGZPX6	Hepatocellular carcinoma	2C12.02	Phase 3	[1]
Sulfatinib	DMPOTM4	Neuroendocrine cancer	2B72.1	Phase 3	[7]
Taberminogene vadenovec	DMW5PHL	Vascular restinosis	BE2Z	Phase 3	[8]
MGCD516	DM752PU	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[9]
Famitinib	DMSFWT7	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
VATALANIB	DMY0UEQ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[11]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[12]
IMC-3C5	DMXI5ON	Solid tumour/cancer	2A00-2F9Z	Phase 1	[13]
JNJ-26483327	DMSQ3AZ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pyrimidine derivative 15	DMV2Y84	N. A.	N. A.	Patented	[15]

20 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	[11]
(5-Phenyl-oxazol-2-yl)-m-tolyl-amine	DM1R5SF	Discovery agent	N.A.	Investigative	[11]
2-(5-Phenyl-oxazol-2-ylamino)-benzonitrile	DMX6QMT	Discovery agent	N.A.	Investigative	[11]
3,6-Di-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine	DMNV0EZ	Discovery agent	N.A.	Investigative	[16]
3-(5-Phenyl-oxazol-2-ylamino)-benzonitrile	DMPBLM2	Discovery agent	N.A.	Investigative	[11]
4-(5-Phenyl-oxazol-2-ylamino)-benzenesulfonamide	DM3N9O5	Discovery agent	N.A.	Investigative	[11]
4-Chloro-N-(2-chloro-benzoyl)-benzenesulfonamide	DMVJ61A	Discovery agent	N.A.	Investigative	[17]
4-Chloro-N-(2-methyl-benzoyl)-benzenesulfonamide	DM6SI78	Discovery agent	N.A.	Investigative	[17]
4-Chloro-N-(3-chloro-benzoyl)-benzenesulfonamide	DMI3OR9	Discovery agent	N.A.	Investigative	[17]
4-Chloro-N-(4-chloro-benzoyl)-benzenesulfonamide	DMTDX2S	Discovery agent	N.A.	Investigative	[17]
4-Chloro-N-(4-nitro-benzoyl)-benzenesulfonamide	DMM0TL6	Discovery agent	N.A.	Investigative	[17]
Anti-VEGFR 3 mab	DMAJ6TC	Discovery agent	N.A.	Investigative	[9]
CB-676475	DMXON4L	Discovery agent	N.A.	Investigative	[18]
CEP-6331	DMNXBTD	Discovery agent	N.A.	Investigative	[19]
N-(2,4-Dichloro-benzoyl)-benzenesulfonamide	DMHI4Y6	Discovery agent	N.A.	Investigative	[17]
N-(3-Bromo-benzoyl)-4-chloro-benzenesulfonamide	DMOQ08F	Discovery agent	N.A.	Investigative	[17]
Phenyl-(5-phenyl-oxazol-2-yl)-amine	DMR2B4O	Discovery agent	N.A.	Investigative	[11]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[20]
SAR-131675	DMSYE4W	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]
[3-(5-Phenyl-oxazol-2-ylamino)-phenyl]-methanol	DMD0LCU	Discovery agent	N.A.	Investigative	[11]

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	6.00E-01	-0.04	-0.23
Prostate cancer	2C82	Prostate	8.36E-03	0.45	0.97
Lung cancer	2C82	Lung tissue	4.66E-60	-0.64	-1.74
Rectal cancer	2C82	Rectal colon tissue	3.75E-02	0.12	1.23
Renal cancer	2C82	Kidney	7.15E-01	-0.17	-0.69
Myelodysplastic syndrome	2C82	Bone marrow	9.59E-01	-0.06	-0.41
Breast cancer	2C82	Breast tissue	1.41E-35	-0.31	-0.93
Acute myelocytic leukaemia	2C82	Bone marrow	7.70E-03	0.02	0.12
Head and neck cancer	2C82	Head and neck tissue	1.14E-01	0.04	0.17

References

• [1] Company report (Medigen)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
• [3] Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006.
• [4] Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13.
• [5] 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.
• [6] 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.
• [7] Clinical pipeline report, company report or official report of Hutchison Medi Pharma.
• [8] Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20.
• [9] 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. (Target id: 1814).
• [10] Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
• [11] Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors. J Med Chem. 2005 Mar 10;48(5):1610-9.
• [12] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [13] Bevacizumab and breast cancer: what does the future hold . Future Oncol. 2012 April; 8(4): 403-414.
• [14] National Cancer Institute Drug Dictionary (drug id 596693).
• [15] VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016).Expert Opin Ther Pat. 2017 Sep;27(9):987-1004.
• [16] Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors. Bioorg Med Chem Lett. 2002 Oct 7;12(19):2767-70.
• [17] Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents. J Med Chem. 2004 Oct 21;47(22):5367-80.
• [18] Synthesis of a novel biotin-tagged photoaffinity probe for VEGF receptor tyrosine kinases. Bioorg Med Chem Lett. 2006 Jan 1;16(1):129-33.
• [19] Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-linea... J Med Chem. 2008 Sep 25;51(18):5680-9.
• [20] The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.