FLT4

Summary

FLT4 (fms related receptor tyrosine kinase 4, HGNC:3767) is a protein-coding gene on chromosome 5q35.3, encoding Vascular endothelial growth factor receptor 3 (P35916). 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.

This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA.

Source: NCBI Gene 2324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart defects, multiple types, 7 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 601 total — 30 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes — 72 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 10 cancer types
• MANE Select transcript: NM_182925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3767
Approved symbol	FLT4
Name	fms related receptor tyrosine kinase 4
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	VEGFR3, PCL, VEGFR-3
Ensembl gene	ENSG00000037280
Ensembl biotype	protein_coding
OMIM	136352
Entrez	2324

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000261937, ENST00000393347, ENST00000424276, ENST00000502293, ENST00000502603, ENST00000502649, ENST00000507059, ENST00000510000, ENST00000512795, ENST00000513527, ENST00000514810, ENST00000619105, ENST00000861588, ENST00000937381, ENST00000955857, ENST00000955858

RefSeq mRNA: 3 — MANE Select: NM_182925 NM_001354989, NM_002020, NM_182925

CCDS: CCDS43412, CCDS4457, CCDS87360

Canonical transcript exons

ENST00000261937 — 30 exons

Exon	Start	End
ENSE00001186304	180601506	180603390
ENSE00002219238	180649488	180649600
ENSE00002235949	180613011	180613110
ENSE00002240553	180619253	180619366
ENSE00002257775	180619665	180619769
ENSE00002499595	180614068	180614179
ENSE00003493921	180630225	180630337
ENSE00003501996	180629696	180629835
ENSE00003509123	180620609	180620715
ENSE00003530114	180625869	180626031
ENSE00003538597	180621542	180621904
ENSE00003553426	180621106	180621252
ENSE00003562906	180626111	180626265
ENSE00003566384	180622731	180622839
ENSE00003568067	180629943	180630105
ENSE00003571346	180619021	180619109
ENSE00003582753	180612506	180612611
ENSE00003594373	180630555	180630799
ENSE00003615754	180611331	180611479
ENSE00003638556	180609905	180610025
ENSE00003645334	180608968	180609053
ENSE00003652996	180631682	180631778
ENSE00003654534	180623935	180624061
ENSE00003668430	180629259	180629427
ENSE00003675036	180616367	180616489
ENSE00003678483	180620173	180620308
ENSE00003681687	180616900	180616994
ENSE00003685911	180618770	180618920
ENSE00003688545	180620876	180621007
ENSE00003692028	180628882	180628999

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 91.43.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3307 / max 154.7193, expressed in 418 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65316	1.7147	317
65317	0.4996	244
65314	0.1164	27

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	91.43	gold quality
left lobe of thyroid gland	UBERON:0001120	90.94	gold quality
thyroid gland	UBERON:0002046	89.67	gold quality
apex of heart	UBERON:0002098	87.85	gold quality
right lung	UBERON:0002167	87.47	gold quality
upper lobe of left lung	UBERON:0008952	87.43	gold quality
sural nerve	UBERON:0015488	87.37	gold quality
omental fat pad	UBERON:0010414	87.27	gold quality
peritoneum	UBERON:0002358	87.21	gold quality
upper lobe of lung	UBERON:0008948	86.59	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.00	gold quality
spleen	UBERON:0002106	85.21	gold quality
metanephros cortex	UBERON:0010533	84.57	gold quality
buccal mucosa cell	CL:0002336	83.44	gold quality
right uterine tube	UBERON:0001302	83.39	gold quality
left uterine tube	UBERON:0001303	82.85	gold quality
body of uterus	UBERON:0009853	82.82	gold quality
left adrenal gland cortex	UBERON:0035825	82.73	gold quality
left adrenal gland	UBERON:0001234	82.29	gold quality
right adrenal gland	UBERON:0001233	82.23	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.34	gold quality
adrenal cortex	UBERON:0001235	81.27	gold quality
adrenal gland	UBERON:0002369	81.16	gold quality
right adrenal gland cortex	UBERON:0035827	81.10	gold quality
endocervix	UBERON:0000458	80.80	gold quality
ectocervix	UBERON:0012249	80.69	gold quality
adenohypophysis	UBERON:0002196	80.35	gold quality
mucosa of stomach	UBERON:0001199	79.73	gold quality
placenta	UBERON:0001987	79.46	gold quality
lower esophagus mucosa	UBERON:0035834	79.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	605.03
E-ANND-3	yes	7.94
E-MTAB-9067	yes	7.71
E-MTAB-8271	no	125.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F7, ETS1, ETS2, GLI3, HR, NFATC1, NFKB1, NFKB, NR2F2, PROX1, RBPJ, RELA, TBX1

Literature-anchored findings (GeneRIF, showing 40)

• A potential mechanism involved in hemangioma formation is the alteration of the FLT4 signaling pathway in endothelial and/or pericytic cells. (PMID:11807987)
• VEGF-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. (PMID:11877295)
• Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. (PMID:12048269)
• Vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C are expressed in human colorectal adenocarcinoma. (PMID:12168824)
• generation of endothelial cells from CD34+ cells is associated with expression of VEGFR3 on the cell surface (PMID:12393704)
• Data demonstrate the expression of vascular endothelial growth factor receptor-3 and vascular endothelial growth factor-C on corneal dendritic cells, which implicate a potential relationship between lymphangiogenesis and leukocyte trafficking in the eye. (PMID:12819011)
• the carboxyl-terminal tail of VEGFR-3 provides important regulatory tyrosine phosphorylation sites with potential signal transduction capacity and these sites are differentially used in ligand-induced homo- and heterodimeric receptor complexes (PMID:12881528)
• VEGF-C/flt-4 system can promote vasculogenesis in stroma of breast cancer. The number of Flt-4 positive vessels is closely related to lymph node metastasis. (PMID:14558949)
• Specific VEGFR3 expression, examined in 27 B-CLL samples, was positive in 26 of them. The VEGF transduction pathway may be very active in CLL cells. Both its paracrine & autocrine pathways may contribute to their enhanced survival. (PMID:14687619)
• VEGF-C and its receptor FLT-4 play a role in the development of gastric cancer, and the tumors with expression of VEGF-C and FLT-4 are more likely to have lymph node metastasis. (PMID:14760756)
• VEGFR-3 may protect against oxidative damage in endothelial cells, and that patients with hereditary lymphoedema may be susceptible to ROS-induced cell damage. (PMID:15102829)
• expression levels were significantly elevated in primary prostatic tumors with sentinel lymph node involvement compared to those lacking lymph node involvement (PMID:15107801)
• vascular endothelial growth factor receptor-3 may have a role in lymph node metastasis in prostate cancer (PMID:15297417)
• integrin alpha5beta1 participates in the activation of both VEGFR-3 and its downstream PI3 kinase/Akt signaling pathway, which is essential for fibronectin-mediated lymphatic endothelial cell survival and proliferation. (PMID:15389531)
• VEGFR-3 needs to be associated to VEGFR-2 to induce ligand-dependent cellular responses (PMID:15474514)
• Patients with primary lymphedema have serum level of VEGF-D significantly higher than controls.The increased levels of VEGF-D suggest that primary lymphedema may be based on defective stimulation of VEGFR-3. (PMID:15693535)
• Ang1 has a role in lymphatic vessel endothelial proliferation, Tie2 expression, and VEGFR-3 upregulation (PMID:15746084)
• KSHV gB can activate VEGFR-3 on the microvascular endothelium and modulate endothelial cell migration and proliferation via an interaction between the alpha3beta1 integrin and the VEGFR-3 receptor (PMID:15878864)
• increased expression of VEGF-C and VEGFR-3 play a role in prostate cancer progression and in metastasis to regional lymph nodes (PMID:15880525)
• There was a close correlation between the expressions of VEGFR-3, CD31 and prostate tumor metastases. (PMID:16044920)
• Overexpression of vascular endothelial growth factor receptor 3 is associated with lung adenocarcinoma (PMID:16116610)
• VEGF-C and its receptor FLT-4 play an important role in the lymphatic metastasis of laryngeal and hypopharyngeal squamous cell carcinoma. (PMID:16375119)
• VEGFR-3/flt4 was expressed in cancer stromal cells. (PMID:16525637)
• VEGF-D/VEGFR-3 signaling plays a critical role in osteoblast maturation (PMID:16624815)
• The VEGF-3/VEGFR-c ratio was positively associated with lymph node metastasis in non-small cell lung cancer . (PMID:16755294)
• multiple myeloma cells (but not B-cell chronic lymphocytic leukemia cells) induced a dramatic increase in expression of VEGFR-1 and VEGFR-3 on human bone marrow endothelial cells (PMID:16959214)
• These results suggest that the expression of VEGFRs and NRPs on keratinocytes may constitute important regulators for its activity and may possibly be responsible for the autocrine signaling in the epidermis. (PMID:17088944)
• This is the first report of an exon 22 mutation of VEGFR3 in Milroy disease. (PMID:17458866)
• VEGFR-3 may play a role in the abnormal endometrial angiogenesis of idiopathic menorrhagia. (PMID:17487423)
• expression of VEGFR-3(S) is up-regulated in >75% of hepatitis B x antigen positive hepatocellular carcinoma (HCC) nodules; HBxAg may short circuit VEGFR-3(S) signaling in liver cancer (PMID:17539024)
• Both VEGF-A and angiopoietin-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells (PMID:17597103)
• In non-small-cell lung cancer cells, VEGF-C/VEGFR-3 coexpression suggests an autocrine/paracrine loop responsible for a high proliferation rate in tumour cells. (PMID:17686546)
• interaction of CEACAM1 with Prox1 and VEGFR-3 plays a crucial role in tumor lymphangiogenesis and reprogramming of vascular endothelial cells to lymphatic endothelial cells (PMID:17761831)
• Expression of VEGF-C, VEGF-D and their receptor VEGFR-3 in diffuse large B-cell lymphomas. (PMID:17926187)
• data suggest that VEGF-C alters lymphatic endothelial function through a mechanism involving VEGFR-3 (PMID:17935478)
• the spectrum of the VEGFR-3 gene mutations causing HL-I (PMID:17945164)
• Data demonstrate that Notch1 and VEGFR-3 interact genetically, that Notch directly induces VEGFR-3 in blood endothelial cells to regulate vascular development, and that Notch and VEGF signaling may function in tumor lymphangiogenesis. (PMID:17948123)
• Increased expression of VEGFR-3 is associated with acute myeloid leukaemia (PMID:18006056)
• VEGFR-3 was expressed in malignant cells from different subtypes of MM (PMID:18008346)
• VEGFR3 single nucleotide polymorphisms andthe haplotype GC in the VEGFA gene are associated with psoriasis in Koreans (PMID:18094729)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	flt4	ENSDARG00000104453
mus_musculus	Flt4	ENSMUSG00000020357
rattus_norvegicus	Flt4	ENSRNOG00000002511

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Vascular endothelial growth factor receptor 3 — P35916 (reviewed: P35916)

Alternative names: Fms-like tyrosine kinase 4, Tyrosine-protein kinase receptor FLT4

All UniProt accessions (4): B5A927, D6RFF2, E9PD35, P35916

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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’.

Subunit / interactions. Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1.

Subcellular location. Cell membrane. Cytoplasm. Nucleus Cell membrane Cell membrane Secreted.

Tissue specificity. Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.

Post-translational modifications. Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H(2)O(2) is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337.

Disease relevance. Lymphatic malformation 1 (LMPHM1) [MIM:153100] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM1 is an autosomal dominant form with variable expression and severity. Onset is usually at birth or in early childhood but can occur later. Affected individuals manifest lymphedema, predominantly in the lower limbs, and hypoplasia of lymphatic vessels. Additional features are hemangioma and nail dysplasia or papillomatosis. The disease is caused by variants affecting the gene represented in this entry. Hemangioma, capillary infantile (HCI) [MIM:602089] A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. Disease susceptibility is associated with variants affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases. Congenital heart defects, multiple types, 7 (CHTD7) [MIM:618780] An autosomal dominant disorder with incomplete penetrance characterized by congenital developmental abnormalities involving structures of the heart. Common defects include tetralogy of Fallot, pulmonary stenosis or atresia, absent pulmonary valve, right aortic arch, double aortic arch, and major aortopulmonary collateral arteries. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51.

Domain organisation. The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding. The fourth and fifth Ig-like C2-type domains are sufficient for homodimerization. The fifth and seventh Ig-like C2-type domains are required for autophosphorylation and further activation.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P35916-2	1, Long	yes
P35916-1	2, Short
P35916-3	3, sVegfr3

RefSeq proteins (3): NP_001341918, NP_002011, NP_891555* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001824	Tyr_kinase_rcpt_3_CS	Conserved_site
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR041348	VEGFR-2_TMD	Domain
IPR050122	RTK	Family
IPR055229	VEGFR1-3_5th	Domain
IPR055238	VEGFR1-3_N_Ig-like	Domain

Pfam: PF07679, PF07714, PF13927, PF17988, PF21339, PF22854, PF22971

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (119 total): sequence variant 35, strand 13, glycosylation site 12, mutagenesis site 12, modified residue 11, domain 8, disulfide bond 7, sequence conflict 6, splice variant 3, helix 2, binding site 2, topological domain 2, signal peptide 1, chain 1, turn 1, region of interest 1, active site 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4BSJ	X-RAY DIFFRACTION	2.5
4BSK	X-RAY DIFFRACTION	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35916-F1	72.82	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1037 (proton acceptor)

Ligand- & substrate-binding residues (2): 851–859; 879

Post-translational modifications (11): 830, 833, 853, 1063, 1068, 1230, 1231, 1265, 1333, 1337, 1363

Disulfide bonds (7): 51–111, 158–206, 252–310, 445–534, 466–486, 578–653, 699–751

Glycosylation sites (12): 33, 104, 166, 251, 299, 411, 515, 527, 594, 683, 690, 758

Mutagenesis-validated functional residues (12):

Position	Phenotype
446	decreases autophosphorylation on tyrosine residues upon ligand binding; when associated with a-516. abolishes autophosph
516	decreases autophosphorylation on tyrosine residues upon ligand binding; when associated with e-446. abolishes autophosph
737	decreases autophosphorylation on tyrosine residues upon ligand binding. abolishes autophosphorylation on tyrosine residu
879	abolishes enzyme activity.
1063	loss of phosphorylation site. no effect on stimulation of cell proliferation and cell migration.
1068	global loss of autophosphorylation. abolishes stimulation of cell proliferation and cell migration.
1230	loss of phosphorylation site. strongly reduces stimulation of cell proliferation and cell migration.
1231	loss of phosphorylation site. strongly reduces stimulation of cell proliferation and cell migration.
1265	loss of phosphorylation site. no effect on stimulation of cell proliferation and cell migration.
1333	loss of phosphorylation site. reduced autophosphorylation.
1337	reduced autophosphorylation. strongly reduces stimulation of cell proliferation and cell migration.
1363	loss of phosphorylation site. slightly reduced autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-195399	VEGF binds to VEGFR leading to receptor dimerization
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 353 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, TGCGCANK_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_SPROUTING_ANGIOGENESIS, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION

GO Biological Process (28): positive regulation of protein phosphorylation (GO:0001934), positive regulation of endothelial cell proliferation (GO:0001938), vasculature development (GO:0001944), lymph vessel development (GO:0001945), lymphangiogenesis (GO:0001946), sprouting angiogenesis (GO:0002040), respiratory system process (GO:0003016), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of cell population proliferation (GO:0008284), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of endothelial cell migration (GO:0010595), cell migration (GO:0016477), peptidyl-tyrosine phosphorylation (GO:0018108), positive regulation of cell migration (GO:0030335), cellular response to vascular endothelial growth factor stimulus (GO:0035924), vascular endothelial growth factor signaling pathway (GO:0038084), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), positive regulation of JNK cascade (GO:0046330), protein autophosphorylation (GO:0046777), vascular endothelial growth factor receptor signaling pathway (GO:0048010), lung alveolus development (GO:0048286), blood vessel morphogenesis (GO:0048514), regulation of blood vessel remodeling (GO:0060312), positive regulation of ERK1 and ERK2 cascade (GO:0070374), angiogenesis (GO:0001525), protein phosphorylation (GO:0006468), respiratory gaseous exchange by respiratory system (GO:0007585)

GO Molecular Function (13): transmembrane receptor protein tyrosine kinase activity (GO:0004714), vascular endothelial growth factor receptor activity (GO:0005021), ATP binding (GO:0005524), growth factor binding (GO:0019838), protein phosphatase binding (GO:0019903), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
VEGF ligand-receptor interactions	1
Signaling by NOTCH4	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein phosphorylation	3
cellular anatomical structure	3
regulation of protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
system development	1
circulatory system development	1
vasculature development	1
anatomical structure development	1
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
angiogenesis	1
system process	1
respiratory gaseous exchange by respiratory system	1
enzyme-linked receptor protein signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
cell motility	1
peptidyl-tyrosine modification	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
cellular response to growth factor stimulus	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to vascular endothelial growth factor stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
MAPK cascade	1

Protein interactions and networks

STRING

2074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLT4	VEGFD	O43915	999
FLT4	VEGFC	P49767	999
FLT4	VEGFB	P49765	998
FLT4	PGF	P49763	997
FLT4	NRP2	O60462	992
FLT4	KDR	P35968	983
FLT4	PDGFC	Q9NRA1	977
FLT4	CDH5	P33151	943
FLT4	ANGPT2	O15123	938
FLT4	PECAM1	P16284	938
FLT4	LYVE1	Q9Y5Y7	936
FLT4	FLT1	P16057	910
FLT4	GRB2	P29354	910
FLT4	EFNB2	P52799	887
FLT4	FOXC2	Q99958	824

IntAct

40 interactions, top by confidence:

A	B	Type	Score
KDR	FLT4	psi-mi:“MI:0915”(physical association)	0.700
FLT4	KDR	psi-mi:“MI:0915”(physical association)	0.700
FLT4	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.640
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
Vegfc	FLT4	psi-mi:“MI:0407”(direct interaction)	0.440
PKM	FLT4	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FLT4	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
FLT4	ILVBL	psi-mi:“MI:0914”(association)	0.420
FLT4	VEGFC	psi-mi:“MI:0915”(physical association)	0.400
FLT4	CEACAM4	psi-mi:“MI:0915”(physical association)	0.400
CEACAM4	FLT4	psi-mi:“MI:0915”(physical association)	0.400
DUSP19	FLT4	psi-mi:“MI:0915”(physical association)	0.370
FLT4	ATF7IP	psi-mi:“MI:0915”(physical association)	0.370
	ABCD4	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
CLEC4A	RBFOX3	psi-mi:“MI:0914”(association)	0.350
CX3CL1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMEM52B	PIK3R2	psi-mi:“MI:0914”(association)	0.350
RDX	RNF113A	psi-mi:“MI:0914”(association)	0.350

BioGRID (297): FLT4 (Affinity Capture-Western), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS), FLT4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IGV4, A0A8M2B818, A0JM41, A2VD98, B0CLX4, B6ZK77, D3YX43, F1LW30, O00241, O18906, O54901, O88775, O95256, P00545, P04218, P0C673, P10522, P13369, P17948, P21995, P27931, P35916, P35917, P35969, P37301, P42071, P42703, P53767, Q08DK1, Q15762, Q58EG3, Q5DX21, Q5FWR8, Q5R412, Q5U2P2, Q5VJ70, Q6GMZ9, Q6PCB8, Q6X936, Q7TSN7

Diamond homologs: D2IYS2, G3V9H8, O08775, O42127, O73791, O73798, O97799, P00529, P00545, P04048, P05532, P05622, P07333, P07949, P09581, P09619, P10721, P11362, P13369, P16092, P16234, P17948, P18460, P18461, P20786, P21802, P21803, P21804, P22182, P22455, P22607, P23049, P26618, P26619, P33497, P35546, P35590, P35916, P35917, P35918

SIGNOR signaling

40 interactions.

A	Effect	B	Mechanism
FLT4	“up-regulates activity”	FLT4	phosphorylation
sunitinib	down-regulates	FLT4	“chemical inhibition”
SRC	up-regulates	FLT4	phosphorylation
axitinib	down-regulates	FLT4	“chemical inhibition”
nintedanib	down-regulates	FLT4	“chemical inhibition”
“Brivanib alaninate”	down-regulates	FLT4	“chemical inhibition”
lenvatinib	down-regulates	FLT4	“chemical inhibition”
KRN-633	down-regulates	FLT4	“chemical inhibition”
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	down-regulates	FLT4	“chemical inhibition”
motesanib	down-regulates	FLT4	“chemical inhibition”
“pazopanib hydrochloride”	down-regulates	FLT4	“chemical inhibition”
Telatinib	down-regulates	FLT4	“chemical inhibition”
1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea	down-regulates	FLT4	“chemical inhibition”
TBX1	“up-regulates quantity by expression”	FLT4	“transcriptional regulation”
pazopanib	“down-regulates activity”	FLT4	“chemical inhibition”
sunitinib	“down-regulates activity”	FLT4	“chemical inhibition”
regorafenib	“down-regulates activity”	FLT4	“chemical inhibition”
VEGFD	up-regulates	FLT4	binding
VEGFC	up-regulates	FLT4	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 10 cancer types — ANGS, BCC, BLCA, CCRCC, CHRCC, HCC, LUAD, LUSC, NBL, UCEC.

Clinical variants and AI predictions

ClinVar

601 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	31
Uncertain significance	284
Likely benign	94
Benign	115

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1177461	NM_182925.5(FLT4):c.244C>T (p.Arg82Ter)	Pathogenic
16259	NM_182925.5(FLT4):c.2569G>A (p.Gly857Arg)	Pathogenic
16260	NM_182925.5(FLT4):c.3122G>C (p.Arg1041Pro)	Pathogenic
16261	NM_182925.5(FLT4):c.3131T>C (p.Leu1044Pro)	Pathogenic
16263	NM_182925.5(FLT4):c.3104A>G (p.His1035Arg)	Pathogenic
16265	NM_182925.5(FLT4):c.2632G>A (p.Val878Met)	Pathogenic
16267	NM_182925.5(FLT4):c.3316G>A (p.Glu1106Lys)	Pathogenic
1806294	NM_182925.5(FLT4):c.1755C>G (p.Tyr585Ter)	Pathogenic
2445224	NM_182925.5(FLT4):c.3332G>A (p.Gly1111Glu)	Pathogenic
2630521	NM_182925.5(FLT4):c.2815del (p.Leu939fs)	Pathogenic
2636940	NM_182925.5(FLT4):c.3019dup (p.Ser1007fs)	Pathogenic
2664278	NM_182925.5(FLT4):c.2771T>A (p.Met924Lys)	Pathogenic
2664279	NM_182925.5(FLT4):c.3109G>A (p.Asp1037Asn)	Pathogenic
3279269	NM_182925.5(FLT4):c.488_489dup (p.Gly164fs)	Pathogenic
3387754	NM_182925.5(FLT4):c.1657+6T>C	Pathogenic
3390372	NM_182925.5(FLT4):c.985+1G>A	Pathogenic
3778773	NM_182925.5(FLT4):c.1706dup (p.Glu570fs)	Pathogenic
4056442	NM_182925.5(FLT4):c.1548+1G>A	Pathogenic
4082986	NM_182925.5(FLT4):c.541C>T (p.Gln181Ter)	Pathogenic
4258403	NM_182925.5(FLT4):c.2569G>C (p.Gly857Arg)	Pathogenic
4530775	NM_182925.5(FLT4):c.844C>T (p.Arg282Ter)	Pathogenic
4531988	NM_182925.5(FLT4):c.2007C>G (p.Tyr669Ter)	Pathogenic
4620088	NM_182925.5(FLT4):c.2561del (p.Gly854fs)	Pathogenic
4795366	NM_182925.5(FLT4):c.2797G>C (p.Gly933Arg)	Pathogenic
4820636	NM_182925.5(FLT4):c.1389G>A (p.Trp463Ter)	Pathogenic
812611	NM_182925.5(FLT4):c.1083C>G (p.Tyr361Ter)	Pathogenic
812612	NM_182925.5(FLT4):c.89del (p.Pro30fs)	Pathogenic
812613	NM_182925.5(FLT4):c.3332-356_3894-1373del	Pathogenic
812614	NM_182925.5(FLT4):c.3574C>T (p.Gln1192Ter)	Pathogenic
812615	NM_182925.5(FLT4):c.1622dup (p.Gln542fs)	Pathogenic

SpliceAI

6684 predictions. Top by Δscore:

Variant	Effect	Δscore
5:180613009:A:AC	donor_gain	1.0000
5:180613010:C:CC	donor_gain	1.0000
5:180614061:CACT:C	donor_loss	1.0000
5:180614062:ACTC:A	donor_loss	1.0000
5:180614063:CTCA:C	donor_loss	1.0000
5:180614064:TCA:T	donor_loss	1.0000
5:180614065:CACCC:C	donor_loss	1.0000
5:180614066:AC:A	donor_gain	1.0000
5:180614066:ACCCA:A	donor_loss	1.0000
5:180614067:C:G	donor_loss	1.0000
5:180614067:CC:C	donor_gain	1.0000
5:180616351:AATGG:A	donor_gain	1.0000
5:180616365:A:AC	donor_gain	1.0000
5:180616366:C:CC	donor_gain	1.0000
5:180616366:CA:C	donor_gain	1.0000
5:180616366:CACTG:C	donor_gain	1.0000
5:180616371:C:A	donor_gain	1.0000
5:180616485:ATGCA:A	acceptor_gain	1.0000
5:180616486:TGCA:T	acceptor_gain	1.0000
5:180616487:GCA:G	acceptor_gain	1.0000
5:180616488:CA:C	acceptor_gain	1.0000
5:180616488:CAC:C	acceptor_gain	1.0000
5:180616490:C:CC	acceptor_gain	1.0000
5:180616490:CTG:C	acceptor_loss	1.0000
5:180616495:G:C	acceptor_gain	1.0000
5:180616495:G:GC	acceptor_gain	1.0000
5:180616498:C:CT	acceptor_gain	1.0000
5:180618766:TCACC:T	donor_loss	1.0000
5:180618767:CACCT:C	donor_loss	1.0000
5:180618768:A:AC	donor_gain	1.0000

AlphaMissense

8932 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:180614107:A:G	W1098R	1.000
5:180614107:A:T	W1098R	1.000
5:180614161:A:G	W1080R	1.000
5:180614161:A:T	W1080R	1.000
5:180616422:T:A	D1055V	1.000
5:180616422:T:C	D1055G	1.000
5:180616422:T:G	D1055A	1.000
5:180616423:C:G	D1055H	1.000
5:180616424:A:C	C1054W	1.000
5:180616460:G:C	N1042K	1.000
5:180616460:G:T	N1042K	1.000
5:180616476:T:A	D1037V	1.000
5:180616476:T:G	D1037A	1.000
5:180619324:A:G	L897P	1.000
5:180619336:A:G	L893P	1.000
5:180619675:T:A	K879N	1.000
5:180619675:T:G	K879N	1.000
5:180619676:T:A	K879I	1.000
5:180619742:C:T	G857E	1.000
5:180619743:C:A	G857W	1.000
5:180619744:G:C	F856L	1.000
5:180619744:G:T	F856L	1.000
5:180619746:A:G	F856L	1.000
5:180629714:C:A	W266C	1.000
5:180629714:C:G	W266C	1.000
5:180614091:A:G	L1103P	0.999
5:180614098:C:A	G1101W	0.999
5:180614112:T:A	D1096V	0.999
5:180614113:C:G	D1096H	0.999
5:180614114:A:C	S1095R	0.999

dbSNP variants (sampled 300 via entrez): RS1000002539 (5:180641598 C>T), RS1000019772 (5:180606902 A>AAC), RS1000046739 (5:180606601 T>C), RS1000053751 (5:180613486 A>C), RS1000190222 (5:180609016 T>C), RS1000201963 (5:180630966 C>G,T), RS1000202666 (5:180640039 A>C), RS1000204443 (5:180602479 C>G), RS1000215415 (5:180636879 G>A), RS1000285762 (5:180608841 C>A,G,T), RS1000299754 (5:180647965 A>G), RS1000312574 (5:180631194 C>A,T), RS1000330474 (5:180647714 A>T), RS1000339456 (5:180613415 G>A), RS1000344908 (5:180645418 G>A)

Disease associations

OMIM: gene MIM:136352 | disease phenotypes: MIM:153100, MIM:618780, MIM:114500, MIM:602089, MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphatic malformation 1	Definitive	Autosomal dominant
capillary infantile hemangioma	Strong	Autosomal dominant
congenital heart defects, multiple types, 7	Strong	Autosomal dominant
tetralogy of fallot	Supportive	Autosomal dominant
lymphatic malformation	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart defects, multiple types, 7	Definitive	AD
lymphatic malformation 1	Definitive	AD

Mondo (11): lymphatic malformation 1 (MONDO:0007919), lymphedema (MONDO:0019297), congenital heart defects, multiple types, 7 (MONDO:0032913), colorectal cancer (MONDO:0005575), capillary infantile hemangioma (MONDO:0011191), colon carcinoma (MONDO:0002032), teratoma (MONDO:0002601), blepharospasm-oromandibular dystonia syndrome (MONDO:0019772), non-immune hydrops fetalis (MONDO:0009369), tetralogy of fallot (MONDO:0008542), lymphatic malformation (MONDO:0019313)

Orphanet (7): Milroy disease (Orphanet:79452), Blepharospasm-oromandibular dystonia syndrome (Orphanet:93964), Non-immune hydrops fetalis (Orphanet:363999), OBSOLETE: Lymphedema (Orphanet:79383), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Infantile capillary hemangioma (Orphanet:464293), OBSOLETE: Familial capillary hemangioma (Orphanet:91415)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000233	Thin vermilion border
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000337	Broad forehead
HP:0000520	Proptosis
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000962	Hyperkeratosis
HP:0001004	Lymphedema
HP:0001015	Prominent superficial veins
HP:0001028	Hemangioma
HP:0001055	Erysipelas
HP:0001156	Brachydactyly
HP:0001328	Specific learning disability
HP:0001511	Intrauterine growth retardation
HP:0001636	Tetralogy of Fallot
HP:0001642	Pulmonic stenosis
HP:0001785	Ankle swelling
HP:0001790	Nonimmune hydrops fetalis
HP:0001999	Abnormal facial shape
HP:0002619	Varicose veins
HP:0002624	Abnormal venous morphology
HP:0003550	Predominantly lower limb lymphedema
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003759	Hypoplasia of lymphatic vessels

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006137_9	Serum folate levels	7.000000e-06
GCST006585_1080	Blood protein levels	6.000000e-13
GCST90002401_31	Platelet distribution width	4.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008209	Lymphedema	C15.604.496
D008538	Meige Syndrome	C10.228.140.079.590; C10.228.662.300.500
D013724	Teratoma	C04.557.465.910
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C535860	Hemangioma, capillary infantile (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1955 (SINGLE PROTEIN), CHEMBL2095227 (PROTEIN FAMILY), CHEMBL2111409 (SELECTIVITY GROUP), CHEMBL3301389 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

72 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 416,441 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL3039504	NINTEDANIB ESYLATE	4	659
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL4303214	FRUQUINTINIB	4	732
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL608533	MIDOSTAURIN	4
CHEMBL939	GEFITINIB	4
CHEMBL101253	VATALANIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL276711	SEMAXANIB	3
CHEMBL290352	CEP-1347	3
CHEMBL300138	ENZASTAURIN	3
CHEMBL377300	BRIVANIB	3
CHEMBL4297190	SURUFATINIB	3
CHEMBL491473	CEDIRANIB	3

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs307821	Efficacy	3	sunitinib	Renal Cell Carcinoma
rs307826	Efficacy	3	sunitinib	Renal Cell Carcinoma

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs307805	FLT4		0.00	0
rs307821	FLT4, SCGB3A1	3	2.25	1	sunitinib
rs307822	FLT4		0.00	0
rs307826	FLT4	3	2.75	1	sunitinib
rs6877011	FLT4		0.00	0
rs7709359	FLT4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

Most potent curated ligand interactions (29 total), top 25:

Ligand	Action	Affinity	Parameter
tivozanib	Inhibition	9.62	pIC50
fruquintinib	Inhibition	9.3	pIC50
catequentinib	Inhibition	9.0	pIC50
sitravatinib	Inhibition	8.7	pIC50
foretinib	Inhibition	8.55	pIC50
cediranib	Inhibition	8.52	pIC50
dovitinib	Inhibition	8.52	pIC50
compound 8i [PMID: 22765894]	Inhibition	8.52	pIC50
compound 8h [PMID: 22765894]	Inhibition	8.49	pIC50
lenvatinib	Inhibition	8.28	pIC50
motesanib	Inhibition	8.22	pIC50
tesevatinib	Inhibition	8.06	pIC50
ibcasertib	Inhibition	8.05	pIC50
sunitinib	Inhibition	8.05	pIC50
tafetinib	Inhibition	7.92	pIC50
nintedanib	Inhibition	7.89	pIC50
RIPK1 inhibitor 22b	Inhibition	7.7	pIC50
sorafenib	Inhibition	7.7	pIC50
pexmetinib	Inhibition	7.38	pIC50
ilorasertib	Inhibition	7.37	pIC50
pazopanib	Inhibition	7.33	pIC50
MK-2461	Inhibition	7.11	pIC50
compound 38k [PMID: 34351741]	Inhibition	6.96	pIC50
CHMFL-KIT-64	Inhibition	6.92	pIC50
VEGF receptor tyrosine kinase inhibitor III	Inhibition	6.9	pIC50

Binding affinities (BindingDB)

118 measured of 130 human assays (142 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
tert-butyl N-[1-[4-[[4-[2-[2-(1-carbamoylcyclopropyl)phenyl]ethyl]-5-chloropyrimidin-2-yl]amino]phenyl]ethyl]carbamate	IC50	2 nM	US-9238644: VEGFR3 inhibitors
2-amino-1-ethyl-7-(3-hydroxy-3-thiophen-3-ylbut-1-ynyl)-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	2 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
FIIN-1	KD	2.8 nM
1-[2-[2-[2-[(1-methylpyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	3 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	3 nM	US-9238644: VEGFR3 inhibitors
FRIN-1	KD	3.1 nM
1-[2-[2-[5-chloro-2-[(1-propan-2-ylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	4 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	4 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	5 nM	US-9238644: VEGFR3 inhibitors
2-amino-1-cyclohexyl-7-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	5 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-amino-1-ethyl-7-[3-hydroxy-3-(3-methoxyphenyl)but-1-ynyl]-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	6 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
1-[2-[2-[5-chloro-2-[(5-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	7 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[[1-(2,2-difluoroethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	7 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[2-[(1-piperidin-4-ylpyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	7 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	7 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	8 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[5-chloro-2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	9 nM	US-9238644: VEGFR3 inhibitors
BMS-907351	IC50	9.9 nM
1-[2-[2-[2-[4-(1-acetamidoethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	10 nM	US-9238644: VEGFR3 inhibitors
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-1,2-thiazole-4-carboxamide	IC50	10.1 nM	US-9446026: Ocular formulations for drug-delivery to the posterior segment of the eye
1-[2-[2-(2-anilino-5-chloropyrimidin-4-yl)ethyl]phenyl]cyclopropane-1-carboxamide	IC50	11 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	12 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[5-chloro-2-[(1-piperidin-4-ylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	12 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-methyl-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	12 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-methyl-2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	13 nM	US-9238644: VEGFR3 inhibitors
2-amino-1-ethyl-7-(3-hydroxy-3-phenyl-but-1-ynyl)-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	14 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-[2-[2-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	15 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[2-[(1-methylpyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	15 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[2-(pyrazolidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	17 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-(pyridazin-4-ylamino)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	20 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-chloro-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	21 nM	US-9238644: VEGFR3 inhibitors
2-amino-1-ethyl-7-[2-(1-hydroxycyclobutyl)ethynyl]-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	21 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-[2-[2-[2-[[1-(1-acetylpiperidin-4-yl)pyrazol-4-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	22 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[2-[4-(1-aminoethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	22 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[5-methyl-2-[[6-(1-methylpiperidin-4-yl)-3-pyridinyl]amino]pyrimidin-4-yl]ethyl]phenyl]cyclopropane-1-carboxamide	IC50	23 nM	US-9238644: VEGFR3 inhibitors
1-[2-[2-[2-(4-piperidin-4-ylanilino)-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]cyclobutane-1-carboxylic acid	IC50	23 nM	US-9238644: VEGFR3 inhibitors
2-amino-1-ethyl-7-[2-(3-hydroxytetrahydrofuran-3-yl)ethynyl]-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	23 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-amino-1-ethyl-7-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	23 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
(2R)-2-[2-[2-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	25 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[2-[[6-(1-methylpiperidin-4-yl)-3-pyridinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	28 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[5-chloro-2-[(6-piperidin-4-yl-3-pyridinyl)amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	31 nM	US-9238644: VEGFR3 inhibitors
(2R)-2-[2-[2-[2-[(1-piperidin-4-ylpyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	31 nM	US-9238644: VEGFR3 inhibitors
2-[2-[2-[5-chloro-2-[[6-(1-methylpiperidin-4-yl)-3-pyridinyl]amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	32 nM	US-9238644: VEGFR3 inhibitors
2-amino-7-(3,4-dihydroxy-3-methyl-but-1-ynyl)-N-methyl-4-oxo-1-tetrahydropyran-4-yl-1,8-naphthyridine-3-carboxamide	IC50	34 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-amino-7-(3-cyclopropyl-3-hydroxy-prop-1-ynyl)-1-ethyl-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	IC50	37 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
2-amino-7-(3-hydroxy-3-methyl-but-1-ynyl)-N-methyl-4-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,8-naphthyridine-3-carboxamide	IC50	40 nM	US-8470847: Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
(2S)-2-[2-[2-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]ethyl]phenyl]propanamide	IC50	41 nM	US-9238644: VEGFR3 inhibitors

ChEMBL bioactivities

1194 potent at pChembl≥5 of 1226 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL3939307
10.00	IC50	0.1	nM	AXITINIB
9.96	IC50	0.11	nM	VANDETANIB
9.90	Ki	0.1259	nM	CHEMBL273187
9.74	IC50	0.18	nM	CHEMBL5403470
9.74	IC50	0.18	nM	CHEMBL5421802
9.70	IC50	0.2	nM	CHEMBL1940109
9.70	Ki	0.1995	nM	CHEMBL404366
9.62	IC50	0.24	nM	TIVOZANIB
9.50	Ki	0.3162	nM	CHEMBL271441
9.50	Ki	0.3162	nM	CHEMBL1986979
9.50	Ki	0.3162	nM	CHEMBL272938
9.46	IC50	0.35	nM	CHEMBL5407330
9.42	IC50	0.38	nM	CHEMBL5412144
9.41	IC50	0.39	nM	CHEMBL5410264
9.40	IC50	0.4	nM	CHEMBL1940108
9.40	Ki	0.3981	nM	CHEMBL1993996
9.40	Ki	0.3981	nM	CHEMBL374044
9.38	IC50	0.42	nM	CHEMBL5394759
9.37	IC50	0.43	nM	CHEMBL5421149
9.30	IC50	0.5	nM	CHEMBL1668411
9.27	IC50	0.54	nM	CHEMBL5436823
9.25	IC50	0.56	nM	CHEMBL6146585
9.24	IC50	0.58	nM	CHEMBL5393865
9.24	IC50	0.58	nM	CHEMBL5410108
9.17	IC50	0.68	nM	CHEMBL6146128
9.17	IC50	0.67	nM	CHEMBL6103505
9.15	IC50	0.7	nM	STAUROSPORINE
9.14	IC50	0.73	nM	CHEMBL2012519
9.10	IC50	0.8	nM	CHEMBL5403747
9.10	IC50	0.8	nM	CHEMBL1173411
9.10	Ki	0.7943	nM	CHEMBL373798
9.10	Ki	0.7943	nM	CHEMBL402846
9.10	Ki	0.7943	nM	CHEMBL1994638
9.06	IC50	0.87	nM	CHEMBL5411025
9.05	IC50	0.9	nM	STAUROSPORINE
9.00	IC50	1	nM	CHEMBL3891581
9.00	IC50	1	nM	AT-9283
9.00	IC50	1	nM	CHEMBL5176837
9.00	IC50	1	nM	SURUFATINIB
9.00	Ki	1	nM	CHEMBL1996255
9.00	Ki	1	nM	CHEMBL403402
8.99	IC50	1.03	nM	CHEMBL5408069
8.96	IC50	1.1	nM	TAK-593
8.96	IC50	1.1	nM	CHEMBL193306
8.96	IC50	1.1	nM	CHEMBL4453304
8.96	IC50	1.1	nM	CHEMBL6142589
8.95	IC50	1.13	nM	CHEMBL2012519
8.94	IC50	1.14	nM	CHEMBL5433332
8.92	IC50	1.2	nM	CHEMBL4303275

PubChem BioAssay actives

711 with measured affinity, of 2691 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Vandetanib	1895650: Inhibition of VEGFR3 (unknown origin)	ic50	0.0001	uM
N-methyl-2-[[3-(2-pyridin-2-ylethyl)-2H-indazol-6-yl]sulfanyl]benzamide	1331764: Inhibition of VEGFR3 (unknown origin)	ic50	0.0001	uM
Axitinib	1424500: Inhibition of VEGFR3 (unknown origin)	ic50	0.0001	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(1-cyclopentylpyrazol-4-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0002	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(3-fluoro-4-methylphenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0002	uM
2-[4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]oxypyrazol-1-yl]-N-(3-methoxyphenyl)acetamide	639906: Inhibition of VEGFR3 phosphorylation by cell based assay	ic50	0.0002	uM
Tivozanib	2159214: Inhibition of VEGFR-3 phosphorylation in serum starved human HUVEC cells incubated for 1 hr by immunoblotting analysis	ic50	0.0002	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-[4-(trifluoromethoxy)phenyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0003	uM
N-[5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrol-3-yl]-3-(4-methylpiperazin-1-yl)propanamide	1155231: Binding affinity to VEGFR3 (unknown origin)	ki	0.0003	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(4-methylphenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0004	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(1-propan-2-ylpyrazol-4-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0004	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0004	uM
1-[2-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(1-propan-2-ylpyrazol-4-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0004	uM
2-[4-(6,7-dimethoxyquinazolin-4-yl)oxypyrazol-1-yl]-N-(3-methoxyphenyl)acetamide	639906: Inhibition of VEGFR3 phosphorylation by cell based assay	ic50	0.0004	uM
(4S,6Z,9S,10R,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	568311: Inhibition of human recombinant VEGFR3 in cell free system after 90 mins	ic50	0.0005	uM
1-butyl-3-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0005	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(1-methylindol-5-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0006	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(2-fluoro-5-methylphenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0006	uM
(4S,6Z,9S,10S)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,15,17-tetraene-2,8-dione	1540765: Inhibition of human VEGFR3 using poly[Glu:Tyr] (4:1) substrate and [gamma-33P]-ATP by radiometric biochemical kinase assay	ic50	0.0007	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715340: Inhibition of human FLT4 using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.0007	uM
1-(1-benzofuran-5-yl)-3-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0008	uM
5-[(Z)-[6-[(4-methoxyphenyl)carbamoylamino]-2-oxo-1H-indol-3-ylidene]methyl]-4-methyl-1H-pyrrole-3-carboxylic acid	491749: Inhibition of VEGFR3	ic50	0.0008	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(2,4-dimethoxyphenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0009	uM
6-[7-methoxy-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-pyrrolidin-3-ylpyridin-2-amine	1894589: Inhibition of FLT4 (unknown origin)	ic50	0.0010	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412576: Inhibition of VEGFR3	ic50	0.0010	uM
1-benzyl-3-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0010	uM
N-[2-(dimethylamino)ethyl]-1-[3-[[4-[(2-methyl-1H-indol-5-yl)oxy]pyrimidin-2-yl]amino]phenyl]methanesulfonamide	2131262: Inhibition of VEGFR3 (unknown origin)	ic50	0.0010	uM
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	2136108: Inhibition of VEGFR-3 (unknown origin) in presence of ATP	ic50	0.0010	uM
2,4-difluoro-N-methoxy-5-[[6-(5-methyl-1,3-oxazol-2-yl)-5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide	248164: Inhibition of VEGF-stimulated human umbilical vein endothelial cell proliferation	ic50	0.0011	uM
(10S,12Z,15S,16R)-6,15,16-trihydroxy-4-methoxy-10-methyl-9-oxatricyclo[15.3.1.02,7]henicosa-1(21),2(7),3,5,12,17,19-heptaene-8,14-dione	1540765: Inhibition of human VEGFR3 using poly[Glu:Tyr] (4:1) substrate and [gamma-33P]-ATP by radiometric biochemical kinase assay	ic50	0.0011	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-[(4-fluorophenyl)methyl]urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0011	uM
N-[5-[2-(cyclopropanecarbonylamino)imidazo[1,2-b]pyridazin-6-yl]oxy-2-methylphenyl]-2,5-dimethylpyrazole-3-carboxamide	710631: Inhibition of VEGFR3	ic50	0.0011	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(4-phenylphenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0012	uM
1-[2-chloro-4-[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]oxyphenyl]-3-(1-propan-2-ylpyrazol-4-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0012	uM
2-amino-1-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methylbut-1-ynyl]-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide	1540765: Inhibition of human VEGFR3 using poly[Glu:Tyr] (4:1) substrate and [gamma-33P]-ATP by radiometric biochemical kinase assay	ic50	0.0012	uM
(7Z)-N-[2-(diethylamino)ethyl]-7-(5-fluoro-2-oxo-1H-indol-3-ylidene)-2-methyl-1,4,5,6-tetrahydroindole-3-carboxamide	773007: Inhibition of VEGFR3 (unknown origin)	ic50	0.0013	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624854: Binding constant for FLT4 kinase domain	kd	0.0015	uM
5-[[6-(5-ethyl-1,3,4-oxadiazol-2-yl)-5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-2,4-difluoro-N-methoxybenzamide	248164: Inhibition of VEGF-stimulated human umbilical vein endothelial cell proliferation	ic50	0.0018	uM
2-hydroxy-3-(2-hydroxyanilino)-6-imino-5-oxocyclohexa-1,3-diene-1-carboxamide	735318: Inhibition of Flt4 (unknown origin) after 20 mins by scintillation counting	ic50	0.0018	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(3-fluorophenyl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0020	uM
N-(4-chlorophenyl)-6-(6,7-dimethoxyquinolin-4-yl)oxynaphthalene-1-carboxamide	326912: Inhibition of VEGFR3	ic50	0.0020	uM
N-[4-[2-(3-tert-butylanilino)-1-methylbenzimidazol-5-yl]oxy-2-pyridinyl]acetamide	1255117: Inhibition of VEGFR (unknown origin)	ic50	0.0020	uM
2,4-difluoro-N-methoxy-5-[[6-[5-(methylsulfonylmethyl)-1,3,4-oxadiazol-2-yl]-5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide	248164: Inhibition of VEGF-stimulated human umbilical vein endothelial cell proliferation	ic50	0.0021	uM
2,4-difluoro-N-methoxy-5-[[6-[5-(2-methylpropyl)-1,3,4-oxadiazol-2-yl]-5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide	248164: Inhibition of VEGF-stimulated human umbilical vein endothelial cell proliferation	ic50	0.0021	uM
5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridinyl]-1H-indazole	2118402: Inhibition of human FLT4 by KINOMEscan analysis	ic50	0.0021	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	767461: Inhibition of FLT4 (unknown origin)	ic50	0.0025	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-dibenzofuran-4-ylurea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0025	uM
5-[2-[5-[[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-2-methylphenyl]ethynyl]-N,1-dimethylimidazole-2-carboxamide	601680: Inhibition of human VEGFR3 using poly[Glu:Tyr] by Hotspot assay	ic50	0.0026	uM
1-[2-fluoro-4-(6-methoxy-7-phenylmethoxyquinazolin-4-yl)oxyphenyl]-3-(1-propan-2-ylpyrazol-4-yl)urea	1975504: Inhibition of VEGFR3 (unknown origin)	ic50	0.0027	uM
methyl 3-[N-[4-[acetyl-[3-(dimethylamino)propyl]amino]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indole-6-carboxylate	397050: Inhibition of human VEGFR3	ic50	0.0030	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one	increases expression, decreases expression, decreases phosphorylation, affects reaction	2
ponatinib	decreases activity	2
Arsenic Trioxide	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
fluorene-9-bisphenol	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	affects methylation, decreases methylation	1
lysophosphatidic acid	affects reaction, increases expression	1
caffeic acid	decreases expression, increases reaction	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases activity	1
4-methoxycinnamate methyl ester	decreases expression, increases reaction	1
3-nitrobenzanthrone	decreases expression	1
scriptaid	affects expression	1
kaempferol-3-O-rutinoside	increases phosphorylation, increases reaction	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one	decreases activity	1
SAR131675	decreases reaction, increases phosphorylation	1
Sunitinib	decreases expression	1
Ciclopirox	decreases phosphorylation, decreases reaction	1
Air Pollutants	increases abundance, increases expression	1
Antifungal Agents	decreases reaction, decreases phosphorylation	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Drugs, Chinese Herbal	increases reaction, decreases expression	1
Malathion	increases expression	1

ChEMBL screening assays

717 unique, capped per target: 683 binding, 32 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000445	Binding	Inhibition of human VEGFR3 expressed in baculovirus insect cell system	Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. — J Med Chem
CHEMBL1963812	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FLT4	PubChem BioAssay data set
CHEMBL4013842	ADMET	Inhibition of human FLT4 preincubated for 15 mins followed by peptide substrate addition measured after 3 hrs by caliper capillary electrophoresis method	Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8G4	Abcam HCT 116 FLT4 KO	Cancer cell line	Male
CVCL_B8VY	Abcam MCF-7 FLT4 KO	Cancer cell line	Female
CVCL_B9ID	Abcam A-549 FLT4 KO	Cancer cell line	Male
CVCL_D7Q1	Ubigene A-549 FLT4 KO	Cancer cell line	Male
CVCL_D9F0	Ubigene HEK293 FLT4 KO	Transformed cell line	Female
CVCL_SN76	HAP1 FLT4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

403 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
NCT00852930	PHASE4	COMPLETED	Low Level Laser Treatment and Breast Cancer Related Lymphedema
NCT01068431	PHASE4	COMPLETED	Short Term Effectiveness Study of Juxta-Fit Versus Trico Bandages in the Treatment of Leg Lymphedema
NCT02257970	PHASE4	COMPLETED	Lymphedema Study for Arm or Leg Lymphedema
NCT02375945	PHASE4	COMPLETED	Comparison Between a Non-elastic Falcro Device and Current Method After Total Knee Arthroplasty
NCT03584633	PHASE4	COMPLETED	Effect of Exercise on Indocyanine Green (ICG) Lymphography Imaging
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
NCT07285005	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Efficacy and Safety of KP-001 Compared With Placebo in Patients Aged ≥2 Years With Common VM, Common LM, or KTS/CLOVES Syndrome
NCT00028951	PHASE3	COMPLETED	Fibrin Sealant in Decreasing Lymphedema Following Surgery to Remove Lymph Nodes in Patients With Cancer of the Vulva
NCT00201890	PHASE3	COMPLETED	Trial of Decongestive Lymphatic Therapy for Lymphedema in Women With Breast Cancer DELTA STUDY
NCT00577317	PHASE3	TERMINATED	Flexitouch® Home Maintenance Therapy or Standard Home Maintenance Therapy in Treating Patients With Lower-Extremity Lymphedema Caused by Treatment for Cervical Cancer, Vulvar Cancer, or Endometrial Cancer
NCT02927496	PHASE3	COMPLETED	A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
NCT02929121	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in India
NCT02929134	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in Sri Lanka
NCT04228991	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated LocoRegional Radiotherapy in Breast Cancer
NCT06144164	PHASE3	RECRUITING	A Study of a Comprehensive Prevention Program to Reduce Lymphedema After Axillary Lymph Node Dissection in People With Breast Cancer
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT02010905	PHASE2	UNKNOWN	Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
NCT02335242	PHASE2	COMPLETED	Sildenafil for the Treatment of Lymphatic Malformations
NCT03243019	PHASE2	RECRUITING	Efficacy of Rapamycin in the Treatment of Cervico-facial Lymphatic Malformations
NCT03427619	PHASE2	COMPLETED	OK432 (Picibanil) in the Treatment of Lymphatic Malformations
NCT03972592	PHASE2	COMPLETED	Topical Sirolimus in Cutaneous Lymphatic Malformations
NCT04861064	PHASE2	RECRUITING	Weekly Sirolimus Therapy
NCT05871970	PHASE2	RECRUITING	Safety and Efficacy Study of Intracystic TARA-002 for the Treatment of Lymphatic Malformations in Participants 6 Months to Less Than 18 Years of Age
NCT05983159	PHASE2	RECRUITING	A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT06437158	PHASE2	RECRUITING	Use of Bleomycin in the Sclerotherapy of Lymphatic Malformations for Pediatric Patients
NCT06789913	PHASE2	RECRUITING	A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation
NCT00022204	PHASE2	COMPLETED	Vitamin E and Pentoxifylline in Treating Women With Lymphedema After Radiation Therapy for Breast Cancer
NCT00058851	PHASE2	COMPLETED	Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms
NCT00064857	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors
NCT00077090	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy Compared With Standard Therapy in Treating Chronic Arm Lymphedema in Patients Who Have Undergone Radiation Therapy for Cancer
NCT00155220	PHASE2	UNKNOWN	Treatment of Lymphedema: Application of the Kinesio Taping
NCT00188604	PHASE2	COMPLETED	The Use of Selenium to Treat Secondary Lymphedema - Breast Cancer
NCT00214032	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema
NCT00589121	PHASE2	COMPLETED	Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
NCT00827372	PHASE2	COMPLETED	A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer