Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15797V)

• DOT Name: Vascular endothelial growth factor receptor 2 (KDR)
• Synonyms: VEGFR-2; EC 2.7.10.1; Fetal liver kinase 1; FLK-1; Kinase insert domain receptor; KDR; Protein-tyrosine kinase receptor flk-1; CD antigen CD309
• Gene Name: KDR
• Related Disease: Pulmonary arterial hypertension
• UniProt ID: VGFR2_HUMAN
• PDB ID: 1VR2 ; 1Y6A ; 1Y6B ; 1YWN ; 2M59 ; 2MET ; 2MEU ; 2OH4 ; 2P2H ; 2P2I ; 2QU5 ; 2QU6 ; 2RL5 ; 2X1W ; 2X1X ; 2XIR ; 3B8Q ; 3B8R ; 3BE2 ; 3C7Q ; 3CJF ; 3CJG ; 3CP9 ; 3CPB ; 3CPC ; 3DTW ; 3EFL ; 3EWH ; 3KVQ ; 3S35 ; 3S36 ; 3S37 ; 3U6J ; 3V2A ; 3V6B ; 3VHE ; 3VHK ; 3VID ; 3VNT ; 3VO3 ; 3WZD ; 3WZE ; 4AG8 ; 4AGC ; 4AGD ; 4ASD ; 4ASE ; 5EW3 ; 5OYJ ; 6GQO ; 6GQP ; 6GQQ ; 6XVJ ; 6XVK
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF00047 ; PF13895 ; PF07714 ; PF21339 ; PF17988
• Sequence:
  MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLD
  WLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQD
  YRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWD
  SKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGE
  KLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRS
  DQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPP
  EIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVP
  PQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPY
  PCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGE
  RVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPT
  PVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLT
  VLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNR
  NLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWL
  LLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPL
  GRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVN
  LLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLK
  RRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLA
  SRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDR
  VYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTML
  DCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVS
  CMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDS
  GMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYS
  SEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 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 and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
• Tissue Specificity: Detected in cornea (at protein level). Widely expressed.
• 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)
  PI3K-Akt sig.ling pathway (hsa04151)
  VEGF sig.ling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Proteoglycans in cancer (hsa05205)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  VEGF binds to VEGFR leading to receptor dimerization (R-HSA-195399)
  Integrin cell surface interactions (R-HSA-216083)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Signaling by membrane-tethered fusions of PDGFRA or PDGFRB (R-HSA-9673768)
  Neurophilin interactions with VEGF and VEGFR (R-HSA-194306)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carvedilol	DMHTEAO	Approved	Vascular endothelial growth factor receptor 2 (KDR) increases the Vascular disorders ADR of Carvedilol.	[44]

43 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 Vascular endothelial growth factor receptor 2 (KDR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[12]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[13]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[14]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[13]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[15]
Orlistat	DMRJSP8	Approved	Orlistat decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[17]
Urea	DMUK75B	Approved	Urea decreases the activity of Vascular endothelial growth factor receptor 2 (KDR).	[18]
Romiplostim	DM3U7SZ	Approved	Romiplostim decreases the activity of Vascular endothelial growth factor receptor 2 (KDR).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[21]
Curcumin	DMQPH29	Phase 3	Curcumin affects the expression of Vascular endothelial growth factor receptor 2 (KDR).	[22]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[24]
VAL-083	DM9J5Q4	Phase 3	VAL-083 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[9]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin affects the expression of Vascular endothelial growth factor receptor 2 (KDR).	[26]
STX-140	DMJK5CT	Phase 2	STX-140 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[27]
MK-2461	DM21WBH	Phase 1/2	MK-2461 decreases the activity of Vascular endothelial growth factor receptor 2 (KDR).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[30]
AMEP	DMFELMQ	Phase 1	AMEP decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[32]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Vascular endothelial growth factor receptor 2 (KDR).	[33]
SB-431542	DM0YOXQ	Preclinical	SB-431542 decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[34]
EMBELIN	DMFZO4Y	Terminated	EMBELIN decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[36]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[37]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[38]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[31]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[39]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[40]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[41]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[41]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN affects the expression of Vascular endothelial growth factor receptor 2 (KDR).	[22]
Fascaplysin	DMG5OZP	Investigative	Fascaplysin decreases the expression of Vascular endothelial growth factor receptor 2 (KDR).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol decreases the phosphorylation of Vascular endothelial growth factor receptor 2 (KDR).	[11]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Vascular endothelial growth factor receptor 2 (KDR).	[16]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Vascular endothelial growth factor receptor 2 (KDR).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Vascular endothelial growth factor receptor 2 (KDR).	[29]
Mepacrine	DMU8L7C	Investigative	Mepacrine decreases the phosphorylation of Vascular endothelial growth factor receptor 2 (KDR).	[42]

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