KDR

Summary

KDR (kinase insert domain receptor, HGNC:6307) is a protein-coding gene on chromosome 4q12, encoding Vascular endothelial growth factor receptor 2 (P35968). Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. In precision oncology, KDR R961W confers sensitivity to Regorafenib Anhydrous in Colorectal Adenocarcinoma (CIViC Level C); 3 further curated variant–drug associations are listed below.

Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas.

Source: NCBI Gene 3791 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 254 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes — 172 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 7 cancer types
• MANE Select transcript: NM_002253

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6307
Approved symbol	KDR
Name	kinase insert domain receptor
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	FLK1, VEGFR, VEGFR2, CD309
Ensembl gene	ENSG00000128052
Ensembl biotype	protein_coding
OMIM	191306
Entrez	3791

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263923, ENST00000509309, ENST00000512566, ENST00000647068, ENST00000922964

RefSeq mRNA: 1 — MANE Select: NM_002253 NM_002253

CCDS: CCDS3497

Canonical transcript exons

ENST00000263923 — 30 exons

Exon	Start	End
ENSE00000716015	55094802	55094955
ENSE00000716018	55097662	55097766
ENSE00000716020	55098137	55098272
ENSE00000716022	55098697	55098803
ENSE00000716023	55101897	55102028
ENSE00000716025	55102362	55102508
ENSE00000877915	55082536	55082635
ENSE00000877916	55087607	55087758
ENSE00000877917	55088868	55088973
ENSE00000877918	55089374	55089473
ENSE00000877919	55089691	55089802
ENSE00000877921	55092617	55092714
ENSE00001074496	55104643	55104984
ENSE00001148006	55081956	55082041
ENSE00001171693	55078481	55080163
ENSE00001171700	55125227	55125595
ENSE00001312000	55096229	55096342
ENSE00001608690	55089956	55090078
ENSE00003483371	55114126	55114265
ENSE00003486695	55114874	55115042
ENSE00003487679	55106687	55106810
ENSE00003510376	55110654	55110768
ENSE00003525395	55121097	55121190
ENSE00003526508	55095577	55095665
ENSE00003552422	55105832	55105940
ENSE00003557806	55107737	55107893
ENSE00003594162	55113304	55113481
ENSE00003635728	55118604	55118800
ENSE00003643459	55115281	55115411
ENSE00003650624	55110403	55110566

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 95.98.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8199 / max 154.0461, expressed in 613 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52154	5.5311	606
52151	0.1908	64
52153	0.0980	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	95.98	gold quality
lower lobe of lung	UBERON:0008949	93.84	gold quality
parietal pleura	UBERON:0002400	93.45	gold quality
pericardium	UBERON:0002407	93.33	gold quality
decidua	UBERON:0002450	93.12	gold quality
placenta	UBERON:0001987	92.97	gold quality
adrenal tissue	UBERON:0018303	92.72	gold quality
omental fat pad	UBERON:0010414	92.45	gold quality
peritoneum	UBERON:0002358	92.42	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.27	gold quality
right lobe of thyroid gland	UBERON:0001119	92.18	gold quality
right lung	UBERON:0002167	91.96	gold quality
pleura	UBERON:0000977	91.60	gold quality
body of uterus	UBERON:0009853	91.24	gold quality
left lobe of thyroid gland	UBERON:0001120	91.08	gold quality
thyroid gland	UBERON:0002046	90.79	gold quality
lung	UBERON:0002048	90.27	gold quality
upper lobe of lung	UBERON:0008948	89.70	gold quality
visceral pleura	UBERON:0002401	89.66	gold quality
upper lobe of left lung	UBERON:0008952	89.62	gold quality
adipose tissue	UBERON:0001013	89.24	gold quality
connective tissue	UBERON:0002384	88.57	gold quality
myometrium	UBERON:0001296	88.18	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.89	gold quality
islet of Langerhans	UBERON:0000006	87.81	gold quality
cauda epididymis	UBERON:0004360	87.62	gold quality
adult organism	UBERON:0007023	86.82	gold quality
left uterine tube	UBERON:0001303	86.55	gold quality
metanephros	UBERON:0000081	86.34	gold quality
gall bladder	UBERON:0002110	86.15	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-10137	yes	1824.81
E-MTAB-9388	yes	1316.66
E-MTAB-9067	yes	1291.88
E-CURD-112	yes	1080.53
E-MTAB-9801	yes	983.25
E-HCAD-23	yes	869.03
E-HCAD-24	yes	777.75
E-MTAB-7407	yes	712.19
E-MTAB-8271	yes	689.77
E-HCAD-10	yes	41.28
E-GEOD-135922	yes	34.17
E-MTAB-7316	yes	24.30
E-MTAB-6701	yes	15.35
E-HCAD-9	yes	14.41
E-MTAB-5061	yes	6.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ADM2, ATF6B, CREB1, DLL4, DNMT1, E2F1, EPAS1, ERG, ESR1, ETS1, ETV2, FLI1, FOXC2, FOXH1, FOXM1, FOXO1, FOXO3, GATA2, GATA4, GTF2I, GTF3A, HEY1, HEY2, HHEX, HIF1A, HOXA5, HOXA9, HOXB5, HOXB6, IRX1, ITGAX, KLF10, KLF2, MEF2C, MIXL1, MYB, NANOG, NCOR1, NCOR2, NFE2L2

miRNA regulators (miRDB)

90 targeting KDR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914

Literature-anchored findings (GeneRIF, showing 40)

• vitronectin increased the presence of all four growth factor receptors and most notably, VEGFR-1; in contrast, fibrin decreased all four receptors, especially FGFR-1 and FGFR-2 (PMID:11693202)
• A potential mechanism involved in hemangioma formation is the alteration of the FLK1 signaling pathway in endothelial and/or pericytic cells. (PMID:11807987)
• green tea catechins are novel inhibitors of VEGFR-2 activity. (PMID:11809684)
• Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro. (PMID:11824379)
• In this study we give evidence of Flt-1 and KDR receptors in platelets. (PMID:11852061)
• VEGF, Flt1, and Flk1 can be considered as indicators of the malignancy potential of diffusely infiltrating astrocytomas. The expression of VEGF and the two receptors may be affected by the proliferative activity of tumor cells. (PMID:11908876)
• Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2) (PMID:11960378)
• CLL B cells consistently express VEGFR2 mRNA; co-expression of angiogenic molecules and receptors suggest autocrine pathways of stimulation. (PMID:11986954)
• Expression of vascular endothelial growth factor receptor Flk1/KDR is induced by shear stress through the CT-rich Sp1 binding site. (PMID:12067897)
• KDR plays a key role in regulating the proliferation of HGCC and HVEC. (PMID:12174363)
• findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis; PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors (PMID:12213878)
• The binding of VEGF to its receptor, KDR, is necessary and sufficient to induce the gene expression profile induced by VEGF. (PMID:12426207)
• The expression of vascular endothelial growth factor and its receptors KDR and Flt-1 by gastric carcinoma tissues and cell lines was detected to elucidate the molecular mechanism of this growth factor in promoting tumor growth. (PMID:12439912)
• VEGFR-2 has a role in regulating angiogenesis-related functions [review] (PMID:12456025)
• transcriptional activation of Flk-1 in endothelial cells requires the interaction between HIF-2alpha and Ets-1 (PMID:12464608)
• A set of loop-1 and -3 structures in the novel vascular endothelial growth factor (VEGF) family member, VEGF-ENZ-7, is essential for the activation of this protein’s signaling. (PMID:12551914)
• Fluid shear stress induced upregulation requires Sp1 transcription factor binding to specific response elements in the 5’ regulatory region (PMID:12560084)
• Staining for the receptors VEGFR-1 and VEGFR-2 was positive in large lymphoid cells in stage IV non-Hodgkin lymphoma. (PMID:12607599)
• Gq/11 proteins mediate KDR tyrosine phosphorylation and KDR-mediated HUVEC proliferation through interaction with KDR. (PMID:12670961)
• These data indicate that activation of vascular endothelial growth factor receptor-2 prevents endothelial cell apoptosis by inhibiting p38 MAP kinase phosphorylation and reducing caspase-3 activity. (PMID:12810080)
• in humans: 1) VEGF, KDR, and Flt-1 mRNA are increased by acute systemic exercise; 2) the time course of the VEGF, KDR, and Flt-1 mRNA responses are different from those previously reported in rats (PMID:12949011)
• TNF induces transactivation between Etk and VEGFR2, and Etk directly activates PI3K-Akt angiogenic signaling independent of VEGF-induced VEGFR2-PI3K-Akt signaling pathway. (PMID:14532277)
• Altered expression of vascular endothelial growth factor and FLK-1 receptor in chronically hypoxic carotid body. (PMID:14635716)
• VEGF, VEGFR-1 and VEGFR-2 are concomitantly expressed in pre-B ALL cells. Expression of the receptors is limited to the intra-cytoplasmic compartment and may suggest either internalization or a block in trafficking of the receptor to the surface. (PMID:14654077)
• changing of transcriptional activity of VEGF gene and its receptor FLK-1 indicates an autocrine mechanism of regulation of angiogenic gene activity in the first step of carcinogenesis–low-grade intraepithelial lesions of the uterine cervix (PMID:14674128)
• Specific VEGFR2 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)
• The expression of VEGF and KDR correlates highly with the normal ocular vascularization in humans (PMID:14691147)
• Intact caveolae are required for the VEGF/VEGFR-2-mediated MEK/ERK signaling cascade. (PMID:14704231)
• phosphorylation of Y1214 on VEGFR2 is required to trigger the sequential activation of Cdc42 and SAPK2/p38 and to drive the SAPK2/p38-mediated actin remodeling in stress fibers in endothelial cells exposed to VEGF (PMID:14724572)
• KDR is constitutively phosphorylated and located at the nucleus of VEGF-producing leukemias; a KDR-specific intracellular inhibitor failed to block KDR nuclear IMPORT, but inhibited the constitutive activation of MAPK/Erk and PI3-kinase/AKT pathways (PMID:14726393)
• the level of sVEGFR-2 is lower in active systemic lupus erythematosus than in inactive disease (PMID:14760936)
• maximal P-selectin translocation and subsequent neutrophil adhesion was mediated by VEGF-A(165) on the activation of VEGFR-2/NRP-1 complex and required PAF synthesis. (PMID:14764537)
• Our data support a role for KDR in oviduct angiogenesis. (PMID:14967383)
• VEGF receotor signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death. (PMID:14996703)
• Tgf-beta mediated repression of flk-1/KDR and mediated repression of flk-1/KDR and VEGF signaling involves the inducible formation of inhibitory Hex-GATA signaling Hex-GATA involves the formation of Hex-GATA complexes. (PMID:15016828)
• Shb binds to tyrosine 1175 in the VEGFR-2, which regulates VEGF-induced formation of focal adhesions and cell migration, of which the latter occurs in a phosphatidylinositol 3-kinase-dependent manner (PMID:15026417)
• Nedd4-mediated vascular endothelial growth factor receptor-2 degradation is prevented by Grb10 (PMID:15060076)
• Data suggest that periostin-mediated angiogenesis derives in part from the up-regulation of the vascular endothelial growth factor receptor Flk-1/KDR by endothelial cells through an integrin alpha(v)beta(3)-focal adhesion kinase signaling pathway. (PMID:15082792)
• PPARgamma1 has bifunctional properties in the regulation of KDR gene expression mediated via interaction with both Sp1 and Sp3 (PMID:15111490)
• vascular endothelial growth factor (VEGF) is strongly expressed in villous cytotrophoblast cells and subsequently in Hofbauer cells while its receptors Flt-1 and Flk-1 are found on vasculogenic and angiogenic precursor cells (PMID:15135240)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdr	ENSDARG00000017321
mus_musculus	Kdr	ENSMUSG00000062960
rattus_norvegicus	Kdr	ENSRNOG00000046829

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), 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), 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 2 — P35968 (reviewed: P35968)

Alternative names: Fetal liver kinase 1, Kinase insert domain receptor, Protein-tyrosine kinase receptor flk-1

All UniProt accessions (1): P35968

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD ligands; monomeric in the absence of bound ligands. Can also form heterodimers with FLT1/VEGFR1 and KDR/VEGFR2. Interacts (tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts (tyrosine-phosphorylated active form preferentially) with DAB2IP (via C2 domain and active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and PDCD6. Interacts (via C-terminus domain) with ERN1 (via kinase domain); the interaction is facilitated in a XBP1 isoform 1- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells. Interacts (via juxtamembrane region) with chaperone PDCL3 (via thioredoxin fold region); the interaction leads to increased KDR/VEGFR2 abundance through inhibition of its ubiquitination and degradation. Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the KDR/VEGFR2 C-terminal region. Interacts with isoform 2 of BSG. Interacts with SLC31A1; this interaction is induced upon VEGFA stimulation leading to SLC31A1 and KDR subsequent co-internalization to early endosomes, thereby activating KDR downstream signaling in endothelial cells. (Microbial infection) Interacts with HIV-1 Tat.

Subcellular location. Cell junction. Endoplasmic reticulum. Cell membrane Cell membrane. Cytoplasm. Nucleus. Cytoplasmic vesicle. Early endosome Secreted Secreted.

Tissue specificity. Detected in cornea (at protein level). Widely expressed.

Post-translational modifications. N-glycosylated. Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases. 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 at Tyr-951 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1175 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054, Tyr-1059, Tyr-1175 and Tyr-1214. The inhibitory disulfide bond between Cys-1024 and Cys-1045 may serve as a specific molecular switch for H(2)S-induced modification that regulates KDR/VEGFR2 function.

Disease relevance. 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 a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi’s sarcoma lesions.

Activity regulation. Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by the small molecule PTK inhibitor SU5614 ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide (H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.

Domain organisation. The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P35968-1	1, mbVegfr-2	yes
P35968-2	2, sVegfr-2
P35968-3	3, VEGFR2-712

RefSeq proteins (1): NP_002244* (*=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
IPR009136	VEGFR2_rcpt	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013151	Immunoglobulin_dom	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: PF00047, PF07679, PF07714, PF13895, 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 (187 total): strand 58, helix 23, glycosylation site 18, sequence variant 16, modified residue 15, mutagenesis site 11, turn 10, domain 8, disulfide bond 8, sequence conflict 5, splice variant 4, binding site 2, topological domain 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, active site 1, site 1, transmembrane region 1

Structure

Experimental structures (PDB)

54 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2XIR	X-RAY DIFFRACTION	1.5
3VO3	X-RAY DIFFRACTION	1.52
6GQQ	X-RAY DIFFRACTION	1.52
3VHE	X-RAY DIFFRACTION	1.55
3WZD	X-RAY DIFFRACTION	1.57
3EWH	X-RAY DIFFRACTION	1.6
3VNT	X-RAY DIFFRACTION	1.64
1YWN	X-RAY DIFFRACTION	1.71
3BE2	X-RAY DIFFRACTION	1.75
6XVJ	X-RAY DIFFRACTION	1.78
4ASE	X-RAY DIFFRACTION	1.83
6GQO	X-RAY DIFFRACTION	1.87
3WZE	X-RAY DIFFRACTION	1.9
2P2H	X-RAY DIFFRACTION	1.95
4AG8	X-RAY DIFFRACTION	1.95
6XVK	X-RAY DIFFRACTION	1.99
4AGC	X-RAY DIFFRACTION	2
4ASD	X-RAY DIFFRACTION	2.03
2OH4	X-RAY DIFFRACTION	2.05
6GQP	X-RAY DIFFRACTION	2.09
1Y6A	X-RAY DIFFRACTION	2.1
1Y6B	X-RAY DIFFRACTION	2.1
2QU6	X-RAY DIFFRACTION	2.1
3C7Q	X-RAY DIFFRACTION	2.1
3CJF	X-RAY DIFFRACTION	2.15
3U6J	X-RAY DIFFRACTION	2.15
3EFL	X-RAY DIFFRACTION	2.2
3S35	X-RAY DIFFRACTION	2.2
3CJG	X-RAY DIFFRACTION	2.25
3VID	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35968-F1	71.67	0.24

Antibody-complex structures (SAbDab): 3 — 3S35, 3S36, 3S37

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 (2): 1028 (proton acceptor); 1175 (interaction with shb)

Ligand- & substrate-binding residues (2): 840–848; 868

Post-translational modifications (15): 801, 951, 982, 984, 996, 1054, 1059, 1175, 1214, 1231, 1235, 1238, 1305, 1309, 1319

Disulfide bonds (8): 53–103, 150–200, 246–307, 445–530, 571–642, 688–737, 1024–1045, 1208

Glycosylation sites (18): 46, 66, 96, 143, 158, 245, 318, 374, 395, 511, 523, 580, 613, 619, 631, 675, 704, 721

Mutagenesis-validated functional residues (11):

Position	Phenotype
726	strongly reduced autophosphorylation and activation of map kinases.
731	strongly reduced autophosphorylation and activation of map kinases.
801	abolishes stimulation of nitric oxide synthesis.
868	loss of enzyme activity.
951	abolishes reorganization of the actin cytoskeleton and cell migration in response to vegfa.
996	strongly reduced autophosphorylation. reduces phosphorylation of plcg1.
1045	significantly higher kinase activity.
1054	strongly reduced autophosphorylation. abolishes phosphorylation of downstream signaling proteins; when associated with f
1059	strongly reduced autophosphorylation. abolishes phosphorylation of downstream signaling proteins; when associated with f
1175	abolishes phosphorylation of plcg1 and map kinases in response to vegfa.
1214	loss of phosphorylation site. abolishes reorganization of the actin cytoskeleton in response to vegfa.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-194306	Neuropilin interactions with VEGF and VEGFR
R-HSA-195399	VEGF binds to VEGFR leading to receptor dimerization
R-HSA-216083	Integrin cell surface interactions
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-9673768	Signaling by membrane-tethered fusions of PDGFRA or PDGFRB
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 533 (showing top): PID_SHP2_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYONIC_HEMOPOIESIS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, PID_S1P_S1P1_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_CHEMOTAXIS

GO Biological Process (68): angiogenesis (GO:0001525), ovarian follicle development (GO:0001541), branching involved in blood vessel morphogenesis (GO:0001569), vasculogenesis (GO:0001570), positive regulation of protein phosphorylation (GO:0001934), positive regulation of endothelial cell proliferation (GO:0001938), lymph vessel development (GO:0001945), positive regulation of mesenchymal cell proliferation (GO:0002053), epithelial cell maturation (GO:0002070), endocardium development (GO:0003157), endothelium development (GO:0003158), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of cell population proliferation (GO:0008284), regulation of cell shape (GO:0008360), mesenchymal cell proliferation (GO:0010463), positive regulation of endothelial cell migration (GO:0010595), negative regulation of gene expression (GO:0010629), positive regulation of macroautophagy (GO:0016239), cell migration (GO:0016477), peptidyl-tyrosine phosphorylation (GO:0018108), positive regulation of cell migration (GO:0030335), positive regulation of BMP signaling pathway (GO:0030513), embryonic hemopoiesis (GO:0035162), cellular response to vascular endothelial growth factor stimulus (GO:0035924), vascular endothelial growth factor receptor-2 signaling pathway (GO:0036324), vascular endothelial growth factor signaling pathway (GO:0038084), surfactant homeostasis (GO:0043129), regulation of MAPK cascade (GO:0043408), positive regulation of MAPK cascade (GO:0043410), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of blood vessel endothelial cell migration (GO:0043536), cell fate commitment (GO:0045165), endothelial cell differentiation (GO:0045446), positive regulation of angiogenesis (GO:0045766), protein autophosphorylation (GO:0046777), vascular endothelial growth factor receptor signaling pathway (GO:0048010), lung alveolus development (GO:0048286), post-embryonic camera-type eye morphogenesis (GO:0048597), epithelial cell proliferation (GO:0050673), positive regulation of positive chemotaxis (GO:0050927)

GO Molecular Function (16): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), vascular endothelial growth factor receptor activity (GO:0005021), integrin binding (GO:0005178), ATP binding (GO:0005524), coreceptor activity (GO:0015026), growth factor binding (GO:0019838), vascular endothelial growth factor binding (GO:0038085), identical protein binding (GO:0042802), cadherin binding (GO:0045296), Hsp90 protein binding (GO:0051879), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (18): extracellular region (GO:0005576), nucleus (GO:0005634), endosome (GO:0005768), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell junction (GO:0030054), signaling receptor complex (GO:0043235), membrane raft (GO:0045121), anchoring junction (GO:0070161), sorting endosome (GO:0097443), cytoplasm (GO:0005737), cell surface (GO:0009986), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by VEGF	2
VEGF ligand-receptor interactions	1
Extracellular matrix organization	1
VEGFA-VEGFR2 Pathway	1
Signaling by PDGFR in disease	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
blood vessel morphogenesis	3
anatomical structure development	3
intracellular membrane-bounded organelle	3
endomembrane system	3
cytoplasm	3
protein phosphorylation	2
cell population proliferation	2
cell adhesion molecule binding	2
protein binding	2
endosome	2
anatomical structure formation involved in morphogenesis	1
female gonad development	1
angiogenesis	1
branching morphogenesis of an epithelial tube	1
cell differentiation	1
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
vasculature development	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
epithelial cell development	1
cell maturation	1
heart development	1
epithelium development	1
enzyme-linked receptor protein signaling pathway	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
gene expression	1
regulation of gene expression	1

Protein interactions and networks

STRING

4630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDR	PECAM1	P16284	999
KDR	VEGFC	P49767	999
KDR	VEGFD	O43915	998
KDR	CDH5	P33151	998
KDR	PGF	P49763	998
KDR	VEGFB	P49765	998
KDR	NRP1	O14786	997
KDR	FGF2	P09038	995
KDR	PDGFC	Q9NRA1	994
KDR	CDH17	Q12864	991
KDR	FLT1	P16057	984
KDR	FLT4	P35916	983
KDR	ANGPT1	Q15389	983
KDR	CTNNB1	P35222	981
KDR	PDGFRB	P09619	979

IntAct

142 interactions, top by confidence:

A	B	Type	Score
CDH5	CTNNB1	psi-mi:“MI:0914”(association)	0.930
KDR	VEGFA	psi-mi:“MI:0407”(direct interaction)	0.850
VEGFA	KDR	psi-mi:“MI:0915”(physical association)	0.850
KDR	VEGFA	psi-mi:“MI:0915”(physical association)	0.850
VEGFA	KDR	psi-mi:“MI:0407”(direct interaction)	0.810
VEGFA	KDR	psi-mi:“MI:0915”(physical association)	0.810
KDR	VEGFA	psi-mi:“MI:2364”(proximity)	0.810
KPNA4	MYC	psi-mi:“MI:0915”(physical association)	0.780
KDR	SRC	psi-mi:“MI:0915”(physical association)	0.770
SRC	KDR	psi-mi:“MI:0915”(physical association)	0.770
NRP1	VEGFA	psi-mi:“MI:0915”(physical association)	0.770
KDR	KDR	psi-mi:“MI:0407”(direct interaction)	0.750
HSPG2	KDR	psi-mi:“MI:0407”(direct interaction)	0.720
KDR	HSPG2	psi-mi:“MI:0407”(direct interaction)	0.720
KDR	FLT4	psi-mi:“MI:0915”(physical association)	0.700

BioGRID (188): KDR (Affinity Capture-Western), KDR (Affinity Capture-Western), KDR (Affinity Capture-Western), KDR (Affinity Capture-Western), YWHAG (Affinity Capture-MS), ZSCAN21 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), PALLD (Affinity Capture-MS), AAR2 (Affinity Capture-MS), CARKD (Affinity Capture-MS), ZCCHC6 (Affinity Capture-MS), GATC (Affinity Capture-MS), SH2D2A (Protein-peptide), SRC (Protein-peptide), KDR (Affinity Capture-Western)

ESM2 similar proteins: A2VDZ5, A7SAZ1, B3LV44, B4NJP3, C5IAW9, O08722, O08747, O08775, O14522, O43567, O54965, O60502, O75460, O95185, P06213, P15127, P15208, P28827, P28828, P35918, P35968, P59823, P59824, P60029, Q09499, Q0VD51, Q26261, Q5GIT4, Q5MD89, Q5RCV8, Q5ZLK8, Q66HG0, Q6AY64, Q6DIW0, Q6NZZ3, Q6UX71, Q761X5, Q7T2Z5, Q7YQL9, Q7Z4R8

Diamond homologs: A4FUY1, A6QQC6, A8MVW5, D3YXG0, D3ZB51, D3ZQE1, E9PZ19, O08775, P13595, P13596, P16573, P31809, P35968, P52583, Q00889, Q14CZ8, Q3KPI0, Q4VAH7, Q52KR2, Q62845, Q640R3, Q69Z26, Q9D2Z1, Q9HBG7, Q9UPX0, B0CLX4, D3YX43, Q6GMZ9, Q8N0Z9, Q92626, Q9I7U4, D2IYS2, G3V9H8, O42127, O73791, O73798, O97799, P00529, P00545, P04048

SIGNOR signaling

91 interactions.

A	Effect	B	Mechanism
KDR	up-regulates	PLCG1	binding
KDR	up-regulates	KDR	phosphorylation
VEGFA	up-regulates	KDR	binding
sunitinib	down-regulates	KDR	“chemical inhibition”
axitinib	down-regulates	KDR	“chemical inhibition”
N1’-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	down-regulates	KDR	“chemical inhibition”
DLL4	“down-regulates quantity by repression”	KDR	“transcriptional regulation”
PTPN2	down-regulates	KDR	dephosphorylation
PTPRJ	down-regulates	KDR	dephosphorylation
C25H27N5O4S	down-regulates	KDR	“chemical inhibition”
nintedanib	down-regulates	KDR	“chemical inhibition”
“BMS 794833”	down-regulates	KDR	“chemical inhibition”
(2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol	down-regulates	KDR	“chemical inhibition”
“Brivanib alaninate”	down-regulates	KDR	“chemical inhibition”
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline	down-regulates	KDR	“chemical inhibition”
lenvatinib	down-regulates	KDR	“chemical inhibition”
1-(2,4-difluorophenyl)-3-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-fluorophenyl]urea	down-regulates	KDR	“chemical inhibition”
KRN-633	down-regulates	KDR	“chemical inhibition”
linifanib	down-regulates	KDR	“chemical inhibition”
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	down-regulates	KDR	“chemical inhibition”
motesanib	down-regulates	KDR	“chemical inhibition”
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	down-regulates	KDR	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ALK	5	58.3×	3e-06
Downstream signal transduction	7	54.4×	1e-08
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	5	36.4×	2e-05
Signaling by CSF1 (M-CSF) in myeloid cells	5	35.3×	2e-05
Signaling by VEGF	6	26.9×	9e-06
RET signaling	5	26.5×	5e-05
VEGFA-VEGFR2 Pathway	9	25.6×	1e-08
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	6	19.7×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell migration involved in sprouting angiogenesis	6	69.5×	1e-07
vascular endothelial growth factor receptor signaling pathway	6	51.6×	6e-07
T cell costimulation	6	40.1×	2e-06
peptidyl-tyrosine phosphorylation	5	37.6×	3e-05
epidermal growth factor receptor signaling pathway	8	35.4×	7e-08
positive regulation of blood vessel endothelial cell migration	5	35.0×	3e-05
negative regulation of T cell receptor signaling pathway	5	32.7×	3e-05
ephrin receptor signaling pathway	5	30.7×	4e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 7 cancer types — ANGS, BRCA, CLLSLL, DLBCLNOS, LUAD, PANCREAS, SKIN.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	161
Likely benign	23
Benign	19

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
12317	NM_002253.4(KDR):c.3439C>T (p.Pro1147Ser)	Pathogenic
2426476	NC_000004.11:g.(?55124936)(57368027_?)del	Pathogenic
134612	NM_002253.4(KDR):c.724C>T (p.Leu242Phe)	Likely pathogenic
3062017	NM_002253.4(KDR):c.2614+1G>A	Likely pathogenic

SpliceAI

3267 predictions. Top by Δscore:

Variant	Effect	Δscore
4:55081949:GTCTT:G	donor_loss	1.0000
4:55081950:TCTTA:T	donor_loss	1.0000
4:55081951:CTTA:C	donor_loss	1.0000
4:55081952:TTACC:T	donor_loss	1.0000
4:55081953:T:TG	donor_loss	1.0000
4:55081954:A:AC	donor_gain	1.0000
4:55081954:A:AT	donor_loss	1.0000
4:55081954:AC:A	donor_gain	1.0000
4:55081955:C:CC	donor_gain	1.0000
4:55081955:C:G	donor_loss	1.0000
4:55081955:CC:C	donor_gain	1.0000
4:55082040:TCCT:T	acceptor_loss	1.0000
4:55082041:CC:C	acceptor_loss	1.0000
4:55082041:CCTT:C	acceptor_gain	1.0000
4:55082042:C:CA	acceptor_loss	1.0000
4:55082042:C:CC	acceptor_gain	1.0000
4:55082043:T:A	acceptor_loss	1.0000
4:55082043:T:C	acceptor_gain	1.0000
4:55082044:T:C	acceptor_gain	1.0000
4:55082045:T:TC	acceptor_gain	1.0000
4:55082046:T:C	acceptor_gain	1.0000
4:55082046:T:TC	acceptor_gain	1.0000
4:55082530:A:AC	donor_gain	1.0000
4:55082531:C:CC	donor_gain	1.0000
4:55082531:CTTA:C	donor_gain	1.0000
4:55082532:TTA:T	donor_loss	1.0000
4:55082533:TACAT:T	donor_loss	1.0000
4:55082534:A:AC	donor_gain	1.0000
4:55082534:AC:A	donor_loss	1.0000
4:55082534:ACAT:A	donor_gain	1.0000

AlphaMissense

8939 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:55088951:A:G	W1143R	1.000
4:55088951:A:T	W1143R	1.000
4:55089433:A:C	F1115L	1.000
4:55089433:A:T	F1115L	1.000
4:55089435:A:G	F1115L	1.000
4:55089473:C:T	G1102D	1.000
4:55089709:A:G	W1096R	1.000
4:55089709:A:T	W1096R	1.000
4:55089720:C:T	G1092D	1.000
4:55089721:C:G	G1092R	1.000
4:55089730:A:G	W1089R	1.000
4:55089730:A:T	W1089R	1.000
4:55089737:A:C	S1086R	1.000
4:55089737:A:T	S1086R	1.000
4:55089739:T:G	S1086R	1.000
4:55089782:C:A	W1071C	1.000
4:55089782:C:G	W1071C	1.000
4:55089784:A:G	W1071R	1.000
4:55089784:A:T	W1071R	1.000
4:55090010:G:C	D1046E	1.000
4:55090010:G:T	D1046E	1.000
4:55090011:T:A	D1046V	1.000
4:55090011:T:C	D1046G	1.000
4:55090011:T:G	D1046A	1.000
4:55090012:C:G	D1046H	1.000
4:55090013:A:C	C1045W	1.000
4:55090014:C:T	C1045Y	1.000
4:55090044:A:G	L1035P	1.000
4:55090049:A:C	N1033K	1.000
4:55090049:A:T	N1033K	1.000

dbSNP variants (sampled 300 via entrez): RS1000035685 (4:55083729 C>T), RS10000926 (4:55086610 T>C), RS1000210270 (4:55090817 C>A,T), RS1000210797 (4:55101479 A>G), RS1000265585 (4:55096876 T>C,G), RS1000266371 (4:55092703 G>A,C,T), RS1000267676 (4:55081065 C>G,T), RS1000331534 (4:55080531 A>G), RS1000474540 (4:55115008 T>A,C), RS1000492443 (4:55078693 A>G), RS1000569829 (4:55109989 C>T), RS1000575026 (4:55123224 T>A), RS10006115 (4:55080187 G>A,T), RS1000636714 (4:55082223 A>G), RS1000737101 (4:55126608 A>C,G)

Disease associations

OMIM: gene MIM:191306 | disease phenotypes: MIM:602089, MIM:142623, MIM:614727, MIM:607859, MIM:187500

GenCC curated gene-disease

Disease	Classification	Inheritance
tetralogy of fallot	Strong	Autosomal dominant
pulmonary arterial hypertension	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	AD

Mondo (11): hepatoblastoma (MONDO:0018666), capillary infantile hemangioma (MONDO:0011191), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), primary ovarian failure (MONDO:0005387), prostate cancer (MONDO:0008315), colon carcinoma (MONDO:0002032), TMEM165-congenital disorder of glycosylation (MONDO:0013870), teratoma (MONDO:0002601), tufted angioma (MONDO:0011927), tetralogy of fallot (MONDO:0008542), pulmonary arterial hypertension (MONDO:0015924)

Orphanet (9): Hepatoblastoma (Orphanet:449), Hirschsprung disease (Orphanet:388), Familial prostate cancer (Orphanet:1331), TMEM165-CDG (Orphanet:314667), Tufted angioma (Orphanet:1063), Tetralogy of Fallot (Orphanet:3303), NON RARE IN EUROPE: Infantile capillary hemangioma (Orphanet:464293), OBSOLETE: Familial capillary hemangioma (Orphanet:91415), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

15 total (16 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000233	Thin vermilion border
HP:0000268	Dolichocephaly
HP:0000337	Broad forehead
HP:0000520	Proptosis
HP:0001156	Brachydactyly
HP:0001511	Intrauterine growth retardation
HP:0001636	Tetralogy of Fallot
HP:0003593	Infantile onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004467	Preauricular pit
HP:0005105	Abnormal nasal morphology
HP:0005306	Capillary hemangioma
HP:0009891	Underdeveloped supraorbital ridges
HP:0012329	Tufted angioma

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002698_1	Serum VEGFR2 concentration	5.000000e-25
GCST004549_15	Endometriosis	1.000000e-11
GCST004549_33	Endometriosis	2.000000e-11
GCST004863_132	Mosquito bite size	3.000000e-06
GCST005962_39	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST006585_590	Blood protein levels	6.000000e-21
GCST006979_432	Heel bone mineral density	2.000000e-12
GCST007429_30	Lung function (FVC)	9.000000e-07
GCST007430_29	Peak expiratory flow	8.000000e-07
GCST007432_21	FEV1	3.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
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.)
C536924	Tufted angioma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (13): CHEMBL2095227 (PROTEIN FAMILY), CHEMBL2111336 (SELECTIVITY GROUP), CHEMBL2111375 (SELECTIVITY GROUP), CHEMBL2111409 (SELECTIVITY GROUP), CHEMBL2111428 (SELECTIVITY GROUP), CHEMBL2111434 (SELECTIVITY GROUP), CHEMBL2111439 (PROTEIN FAMILY), CHEMBL2111440 (SELECTIVITY GROUP), CHEMBL2111480 (SELECTIVITY GROUP), CHEMBL279 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

172 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,004,535 (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
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL1091250	INDIGOTINDISULFONATE	4	340
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1200485	SORAFENIB TOSYLATE	4	30,403
CHEMBL1200868	PHENYL AMINOSALICYLATE	4	1,593
CHEMBL1229517	VEMURAFENIB	4	15,704
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
CHEMBL1412	PIPERAZINE	4	645,037
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL146095	GLAFENINE	4	2,714
CHEMBL1567	SUNITINIB MALATE	4	161
CHEMBL1697725	AUROTHIOGLUCOSE	4
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1756	ESTRAMUSTINE PHOSPHATE	4	56
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4
CHEMBL1852688	INFIGRATINIB	4
CHEMBL1873475	IBRUTINIB	4
CHEMBL1946170	REGORAFENIB	4
CHEMBL1983268	ENTRECTINIB	4
CHEMBL1983350	STIRIPENTOL	4
CHEMBL2103868	CABOZANTINIB S-MALATE	4
CHEMBL2105709	QUIZARTINIB DIHYDROCHLORIDE	4
CHEMBL2105717	CABOZANTINIB	4
CHEMBL221959	TOFACITINIB	4

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items; also 1 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
KDR R961W	Regorafenib Anhydrous	Colorectal Adenocarcinoma	Sensitivity/Response	CIViC C	EID1191
KDR A1065T	Sorafenib + Sunitinib	Angiosarcoma	Sensitivity/Response	CIViC D	EID1106
KDR D717V	Sorafenib + Sunitinib	Angiosarcoma	Sensitivity/Response	CIViC D	EID1107
KDR R1032Q	Lenvatinib + Axitinib + Cabozantinib + Dovitinib	Colorectal Cancer	Sensitivity/Response	CIViC D	EID9339

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

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1870377	Efficacy	3	sorafenib	Hepatocellular Carcinoma
rs1870377	Toxicity	3	sorafenib	Hand-foot syndrome;Hypertension
rs2071559	Efficacy	3	sorafenib	Hepatocellular Carcinoma;Renal Cell Carcinoma
rs2239702	Efficacy	3	sorafenib	Renal Cell Carcinoma
rs34231037	Efficacy,Metabolism/PK	3	pazopanib	Kidney Neoplasms
rs4864950	Toxicity	3	sorafenib	Drug Toxicity
rs4864950	Toxicity	3	regorafenib	Drug Toxicity

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1870377	KDR	3	5.00	2	sorafenib
rs2071559	KDR	3	5.75	1	sorafenib
rs2239702	KDR	3	4.00	1	sorafenib
rs2305948	KDR		0.00	0
rs7667298	KDR		0.00	0
rs7671745	KDR		0.00	0
rs34231037	KDR	3	2.00	1	pazopanib
rs4864950	KDR	3	3.50	2	sorafenib;regorafenib

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 (89 total), top 25:

Ligand	Action	Affinity	Parameter
cabozantinib	Inhibition	10.46	pIC50
ramucirumab	Antagonist	10.3	pKd
pulocimab	Binding	9.96	pKd
tivozanib	Inhibition	9.8	pIC50
canlitinib	Inhibition	9.42	pIC50
foretinib	Inhibition	9.1	pIC50
pegdinetanib	Inhibition	9.0	pKd
VEGF receptor tyrosine kinase inhibitor III	Inhibition	9.0	pIC50
rivoceranib	Inhibition	9.0	pIC50
cediranib	Inhibition	8.96	pKd
tesevatinib	Inhibition	8.82	pIC50
compound 13a [PMID: 23639540]	Inhibition	8.77	pIC50
MLKL compound 1	Inhibition	8.7	pIC50
ilorasertib	Inhibition	8.7	pIC50
tinengotinib	Inhibition	8.6	pIC50
BIBF-1202	Inhibition	8.54	pKd
motesanib	Inhibition	8.52	pIC50
dorsomorphin	Inhibition	8.4	pIC50
linifanib	Inhibition	8.4	pIC50
lenvatinib	Inhibition	8.4	pIC50
lucitanib	Inhibition	8.4	pIC50
CEP-11981	Inhibition	8.4	pIC50
compound 8i [PMID: 22765894]	Inhibition	8.4	pIC50
compound 8h [PMID: 22765894]	Inhibition	8.38	pIC50
famitinib	Inhibition	8.3	pIC50

Binding affinities (BindingDB)

3235 measured of 4106 human assays (4123 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
cyclopropyl-[5-[[4-[4-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone	IC50	0.1 nM	US-8871778: Substituted pyrimidine compounds and their use as SYK inhibitors
2,2,2-trifluoro-1-[5-[[6-[4-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]-2-pyridinyl]amino]-1-methylindol-3-yl]ethanone	IC50	0.1 nM	US-8871778: Substituted pyrimidine compounds and their use as SYK inhibitors
N-{4-chloro-3-[(4-methylpiperazin-1-yl)methyl]phenyl}-5-[(6,7-dimethoxyquinolin-4-yl)oxy]-1H-1,3-benzodiazol-2-amine	KI	0.2 nM
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]phenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide	KD	0.21 nM	US-8975282: Substituted pyrazolone compounds and methods of use
N-(3,5-dimethoxyphenyl)-N-(1H-imidazol-5-ylmethyl)-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-2-amine	IC50	0.355 nM	US-9757364: Naphthyridine derivative compounds
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
4-[(8-anilino-9-propan-2-ylpurin-2-yl)amino]-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide	IC50	0.4 nM	US-9096601: Arylamino purine derivatives, preparation method and pharmaceutical use thereof
4-[(8-anilino-9-propan-2-ylpurin-2-yl)amino]-N-(1-methylpiperidin-4-yl)benzamide	IC50	0.4 nM	US-9096601: Arylamino purine derivatives, preparation method and pharmaceutical use thereof
9-cyclopentyl-2-N-[4-(4-methylpiperazin-1-yl)phenyl]-8-N-phenylpurine-2,8-diamine	IC50	0.4 nM	US-9096601: Arylamino purine derivatives, preparation method and pharmaceutical use thereof
N-(2-fluoro-3,5-dimethoxyphenyl)-7-(1-methylpyrazol-4-yl)-N-(1H-pyrazol-5-ylmethyl)-1,5-naphthyridin-2-amine	IC50	0.417 nM	US-9757364: Naphthyridine derivative compounds
1-[3-[7-[6-[(1-hydroxy-2-methylpropan-2-yl)amino]pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.447 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
8-chloro-N-(3,5-dimethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-2-amine	IC50	0.447 nM	US-9757364: Naphthyridine derivative compounds
5-{[(5Z)-4-[(3-chloro-4-fluorophenyl)amino]-6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-5-ylidene]methyl}-N-[3-(diethylamino)-2-hydroxypropyl]-4-methyl-1H-pyrrole-2-carboxamide	IC50	0.45 nM
1-[3-[7-(4-imidazol-1-ylpyrimidin-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.46 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
8-[4-amino-3-[4-[(2-fluoro-5-methylphenyl)carbamoylamino]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]-N-hydroxyoctanamide	IC50	0.47 nM	US-9695181: Hydroximic acid derivatives and medical applications therof
4-[(2-Fluoro-5-hydroxy-4-methylphenyl)amino]-8-({[2-(pyridin-4-yl)ethyl]amino}methyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one	IC50	0.475 nM	US-10047096
1-[3-[7-[6-(3-hydroxypiperidin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.484 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
8-{[Ethyl(methyl)amino]methyl}-4-[(2-fluoro-5-hydroxy-4-methylphenyl)amino]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one	IC50	0.487 nM	US-10047096
1-[3-[7-[5-(cyclopropylamino)-1,3,4-thiadiazol-2-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.5 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-3-fluorophenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide	KD	0.5 nM	US-8975282: Substituted pyrazolone compounds and methods of use
N-(4-chloro-3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)-5-[(6,7-dimethoxyquinazolin-4-yl)oxy]-1,3-benzoxazol-2-amine	KI	0.5 nM
N-(4-chloro-3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)-5-[(6,7-dimethoxyquinolin-4-yl)oxy]-1,3-benzoxazol-2-amine	KI	0.5 nM
N-{4-chloro-3-[(4-methylpiperazin-1-yl)methyl]phenyl}-5-[(6,7-dimethoxyquinolin-4-yl)oxy]-1,3-benzoxazol-2-amine	KI	0.5 nM
N-(3,5-dimethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-2-amine	IC50	0.501 nM	US-9757364: Naphthyridine derivative compounds
1-[3-[7-[6-(3-oxopiperazin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.53 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[6-(4-aminopiperidin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.535 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-(5-amino-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.54 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[1-(oxolan-3-yl)pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.542 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.545 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-(6-piperidin-1-ylpyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.55 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
4-(2-fluoro-3,5-dimethoxy-N-[7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-2-yl]anilino)butanenitrile	IC50	0.55 nM	US-9757364: Naphthyridine derivative compounds
1-[3-[7-[6-(4-acetylpiperazin-1-yl)-3-pyridinyl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.56 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[6-(2-hydroxyethylamino)pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.569 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-(1-piperidin-4-ylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.57 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[1-(1-ethylpyrrolidin-3-yl)imino-3-iminopropan-2-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.582 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
(3S,4R)-1-[[1-[2-[(3-chloro-1,2-dimethylindol-5-yl)amino]pyrimidin-4-yl]-3-methylpyrazol-4-yl]methyl]-4-methoxypyrrolidin-3-ol	IC50	0.6 nM	US-8871778: Substituted pyrimidine compounds and their use as SYK inhibitors
N-[3-[(8-anilino-9-propan-2-ylpurin-2-yl)amino]phenyl]prop-2-enamide	IC50	0.6 nM	US-9096601: Arylamino purine derivatives, preparation method and pharmaceutical use thereof
5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2-methylphenol	IC50	0.6 nM
1-[3-[7-(1-pyrrolidin-3-ylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.603 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[1-imino-3-(1-methylpiperidin-3-yl)iminopropan-2-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.61 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[6-(dimethylamino)pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.61 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-(1-piperidin-3-ylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.612 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[1-imino-3-(1-propan-2-ylazetidin-3-yl)iminopropan-2-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.613 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[4-(cyanomethyl)-1-(1H-indol-7-ylmethyl)piperidin-4-yl]-3-(4-fluoroanilino)pyrazole-4-carboxamide	IC50	0.626 nM	US-10047096
1-[3-[7-[(Z)-1-amino-4-imino-4-morpholin-4-ylbut-1-enyl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.64 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-[5-(2-methoxyethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.643 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
1-[3-[7-(4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-3-(2,2,2-trifluoroethyl)urea	IC50	0.675 nM	US-8796244: Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
N-(3,5-dimethoxyphenyl)-7-(1-methylpyrazol-4-yl)-N-piperidin-4-yl-1,5-naphthyridin-2-amine	IC50	0.676 nM	US-9757364: Naphthyridine derivative compounds
4-[(2-Fluoro-5-hydroxy-4-methylphenyl)amino]-8-{[(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one	IC50	0.68 nM	US-10047096
(3S,4R)-1-[[3-methyl-1-[2-[(1-methyl-3-methylsulfonylindazol-5-yl)amino]pyrimidin-4-yl]pyrazol-4-yl]methyl]pyrrolidine-3,4-diol	IC50	0.7 nM	US-8871778: Substituted pyrimidine compounds and their use as SYK inhibitors

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL3925855
10.70	IC50	0.02	nM	AXITINIB
10.68	Ki	0.021	nM	SORAFENIB
10.64	IC50	0.023	nM	CHEMBL5189340
10.62	Ki	0.024	nM	CHEMBL1254007
10.52	Ki	0.03	nM	CHEMBL3898789
10.52	Ki	0.03	nM	CHEMBL3915607
10.52	IC50	0.03	nM	CHEMBL429743
10.52	IC50	0.03	nM	CABOZANTINIB
10.48	IC50	0.033	nM	CHEMBL1254007
10.46	IC50	0.035	nM	CABOZANTINIB
10.46	IC50	0.035	nM	EXELIXIS
10.46	Ki	0.035	nM	CABOZANTINIB
10.40	Ki	0.04	nM	CHEMBL3899609
10.40	Ki	0.04	nM	CHEMBL3915544
10.40	Ki	0.04	nM	AG-13958
10.36	Ki	0.044	nM	CHEMBL1254007
10.34	Ki	0.046	nM	CHEMBL3952496
10.30	Ki	0.05	nM	CHEMBL3969695
10.22	Ki	0.06	nM	CHEMBL3904168
10.22	Ki	0.06	nM	CHEMBL3891895
10.22	IC50	0.06	nM	SORAFENIB
10.21	IC50	0.062	nM	CHEMBL195218
10.21	Ki	0.062	nM	CHEMBL3984370
10.10	Ki	0.08	nM	CHEMBL3889841
10.10	Ki	0.08	nM	CHEMBL3954818
10.10	Ki	0.08	nM	CHEMBL3912174
10.07	IC50	0.086	nM	CABOZANTINIB
10.03	IC50	0.093	nM	TAK-593
10.03	Ki	0.093	nM	CHEMBL3894732
10.00	Ki	0.1	nM	CHEMBL3891135
10.00	IC50	0.1	nM	AXITINIB
10.00	IC50	0.1	nM	CHEMBL5557999
9.96	Ki	0.11	nM	CHEMBL3959310
9.96	Ki	0.11	nM	CHEMBL3978730
9.96	Ki	0.11	nM	CHEMBL3967940
9.96	Ki	0.11	nM	CHEMBL3960830
9.96	IC50	0.11	nM	CHEMBL5411585
9.92	IC50	0.12	nM	CHEMBL5186748
9.92	Ki	0.12	nM	SORAFENIB
9.89	Ki	0.13	nM	CHEMBL3930485
9.89	Ki	0.13	nM	CHEMBL363042
9.85	IC50	0.14	nM	CHEMBL3093581
9.85	IC50	0.14	nM	CHEMBL3586072
9.85	Ki	0.14	nM	CHEMBL3972140
9.82	IC50	0.15	nM	CHEMBL3586071
9.82	Ki	0.15	nM	CHEMBL3938388
9.80	IC50	0.16	nM	TIVOZANIB
9.80	Ki	0.16	nM	CHEMBL238737
9.80	IC50	0.16	nM	SORAFENIB

PubChem BioAssay actives

3404 with measured affinity, of 6100 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
1-[2-fluoro-4-(5-methylpyrrolo[3,2-d]pyrimidin-4-yl)oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	614641: Inhibition of human N-terminal His-tagged non-phosphorylated VEGFR2 preincubated for 120 mins in presence of ATP by AlphaScreen analysis	ic50	<0.0001	uM
2-decylpyrazolo[3,4-d]pyrimidin-4-amine	578262: Inhibition of human recombinant His-tagged VEGFR2 assessed as infrared absorption	ki	0.0001	uM
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]-N-methylpyridine-2-carboxamide	1231899: Inhibition of VEGFR-2 (unknown origin) after 1 hr by ADP-Glo assay	ic50	0.0001	uM
5-[4-[[3-bromo-5-(trifluoromethyl)phenyl]carbamoylamino]phenyl]-N-methylpyridine-2-carboxamide	1231899: Inhibition of VEGFR-2 (unknown origin) after 1 hr by ADP-Glo assay	ic50	0.0001	uM
4-[[4-(7-chloro-1-methyl-2-oxo-3H-1,4-benzodiazepin-5-yl)phenyl]diazenyl]-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide	2064387: Inhibition of VEGFR2 (unknown origin) using Poly-(Glu,Tyr 4:1) peptide as substrate incubated for 1 hr by ELISA method	ic50	0.0001	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-[4-(trifluoromethyl)phenyl]urea	1975503: Inhibition of VEGFR2 (unknown origin)	ic50	0.0001	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(3-methylphenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0002	uM
1-(4-chlorophenyl)-3-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0002	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(2-methoxyphenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0002	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-phenylurea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0002	uM
N-[4-chloro-3-[(4-methylpiperazin-1-yl)methyl]phenyl]-6-(6,7-dimethoxyquinolin-4-yl)oxy-1H-benzimidazol-2-amine	1797643: HTRF Kinase Inhibition Assay from Article 10.1021/jm070034i: “Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors.”	ki	0.0002	uM
7-(6,7-dimethoxyquinolin-4-yl)oxy-N-(4-methylphenyl)-2,3-dihydro-1,4-benzoxazine-4-carboxamide	325872: Inhibition of KDR by HTRF assay	ic50	0.0002	uM
6-(6,7-dimethoxyquinolin-4-yl)oxy-N-(1,2-oxazol-3-yl)naphthalene-1-carboxamide	326845: Inhibition of KDR by HTRF assay	ic50	0.0002	uM
6-(6,7-dimethoxyquinolin-4-yl)oxy-N-phenylnaphthalene-1-carboxamide	326845: Inhibition of KDR by HTRF assay	ic50	0.0002	uM
1-[3,5-bis(trifluoromethyl)phenyl]-3-(4-pyridin-3-ylphenyl)urea	1231899: Inhibition of VEGFR-2 (unknown origin) after 1 hr by ADP-Glo assay	ic50	0.0002	uM
1-(4-aminopyrazolo[3,4-d]pyrimidin-2-yl)decan-2-ol	578262: Inhibition of human recombinant His-tagged VEGFR2 assessed as infrared absorption	ki	0.0003	uM
6-fluoro-3-[5-(pyridine-4-carbonyl)-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl]-1H-quinolin-2-one	657010: Inhibition of recombinant VEGFR-2 kinase domain by homogeneous time-resolved fluorescence assay	ic50	0.0003	uM
1-[4-(2-aminoquinazolin-7-yl)phenyl]-3-[2-bromo-4-(trifluoromethoxy)phenyl]thiourea	1426700: Inhibition of VEGFR2 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0003	uM
2-hydrazinyl-6-naphthalen-2-yl-4-(4-nitrophenyl)pyridine-3-carbonitrile	2026316: Inhibition of VEGFR-2 (unknown origin) kinase activity using poly(Glu-Tyr) at 4:1 ratio as substrate in presence of ATP incubated for 1 hr by ELISA	ic50	0.0003	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(1-cyclopentylpyrazol-4-yl)urea	1975503: Inhibition of VEGFR2 (unknown origin)	ic50	0.0003	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(4-methylphenyl)urea	1975503: Inhibition of VEGFR2 (unknown origin)	ic50	0.0003	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(2-cyclopentylpyrazol-3-yl)urea	1975503: Inhibition of VEGFR2 (unknown origin)	ic50	0.0003	uM
1-(1-benzofuran-5-yl)-3-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]urea	1975503: Inhibition of VEGFR2 (unknown origin)	ic50	0.0003	uM
(6aR,10aR)-3-(6-bromo-2-methylhexan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol	578262: Inhibition of human recombinant His-tagged VEGFR2 assessed as infrared absorption	ki	0.0004	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(4-fluorophenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0004	uM
1-(2,5-difluorophenyl)-3-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0004	uM
1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(2,4-difluorophenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0004	uM
N-cyclopropyl-6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxamide	326761: Inhibition of KDR	ic50	0.0004	uM
3-chloro-2-(1,3-difluoropropan-2-yloxy)-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]cyclohexa-2,5-diene-1,4-dione	257072: Inhibition of poly(Glu4-Tyr)peptide phosphorylation by recombinant VEGFR2 at 10 uM ATP	ic50	0.0004	uM
4-[5-(cyclopropylcarbamoyl)naphthalen-2-yl]oxy-7-methoxyquinoline-6-carboxamide	326761: Inhibition of KDR	ic50	0.0004	uM
1-[3-bromo-5-(trifluoromethyl)phenyl]-3-(4-pyridin-3-ylphenyl)urea	1231899: Inhibition of VEGFR-2 (unknown origin) after 1 hr by ADP-Glo assay	ic50	0.0004	uM
N-[(Z)-[(E)-1-(4-chlorophenyl)-3-(4-methoxyphenyl)prop-2-enylidene]amino]phthalazin-1-amine	1330727: Inhibition of VEGFR-2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0004	uM
N-[(Z)-[(E)-1,3-diphenylprop-2-enylidene]amino]phthalazin-1-amine	1330727: Inhibition of VEGFR-2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0004	uM
4-(phthalazin-1-ylamino)benzonitrile	1330727: Inhibition of VEGFR-2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0004	uM
2-[3-[[6-[4-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyrimidin-4-yl]amino]phenyl]acetic acid	1782129: Inhibition of GST-6His tagged VEGFR2 (unknown origin) using biotin-aminohexyl-EEEEYFELVAKKKK-NH2 peptide substrate incubated for 90 mins by HTRF assay	ic50	0.0004	uM
1-[2-chloro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]oxyphenyl]-3-(4-phenylphenyl)urea	1975503: Inhibition of VEGFR2 (unknown origin)	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	568314: Inhibition of human recombinant VEGFR2 expressed in Sf9 cells after 60 mins	ic50	0.0005	uM
6-(6,7-dimethoxyquinolin-4-yl)oxy-N-[3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide	326845: Inhibition of KDR by HTRF assay	ic50	0.0005	uM
2-undecylpyrazolo[3,4-d]pyrimidin-4-amine	578262: Inhibition of human recombinant His-tagged VEGFR2 assessed as infrared absorption	ki	0.0005	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(2-fluorophenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0005	uM
N-(4-chlorophenyl)-7-(6,7-dimethoxyquinolin-4-yl)oxy-2,3-dihydro-1,4-benzoxazine-4-carboxamide	325872: Inhibition of KDR by HTRF assay	ic50	0.0005	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(4-methylphenyl)urea	241089: Inhibition of vascular endothelial growth factor receptor 2	ic50	0.0005	uM
6-(6,7-dimethoxyquinolin-4-yl)oxy-N-[4-(trifluoromethyl)phenyl]naphthalene-1-carboxamide	326845: Inhibition of KDR by HTRF assay	ic50	0.0005	uM
N-[4-chloro-3-[(4-methylpiperazin-1-yl)methyl]phenyl]-5-(6,7-dimethoxyquinolin-4-yl)oxy-1,3-benzoxazol-2-amine	1797643: HTRF Kinase Inhibition Assay from Article 10.1021/jm070034i: “Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors.”	ki	0.0005	uM
1-(3-tert-butyl-1,2-oxazol-5-yl)-3-[2-fluoro-5-[7-(methylamino)-2-oxo-1-[(3S)-oxolan-3-yl]-1,6-naphthyridin-3-yl]phenyl]urea	1226870: Inhibition of KDR (unknown origin)	ic50	0.0005	uM
1-[3-(3-amino-1H-indazol-4-yl)phenyl]-3-(3-chlorophenyl)urea	1254828: Inhibition of VEGFR-2 (unknown origin) after 1 hr by ADP-Glo assay	ic50	0.0005	uM
ethyl 4-(phthalazin-1-ylamino)benzoate	1330727: Inhibition of VEGFR-2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0005	uM
6-chloro-3-[5-(2-pyridin-4-ylacetyl)-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl]-1H-quinolin-2-one	657010: Inhibition of recombinant VEGFR-2 kinase domain by homogeneous time-resolved fluorescence assay	ic50	0.0005	uM
4-(3-methylphenyl)-1-[[4-(1H-pyrazol-4-yl)phenyl]methyl]triazole	1623885: Inhibition of VEGFR-2 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0005	uM
N-[4-[1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]triazol-4-yl]phenyl]cyclopropanecarboxamide	1533549: Inhibition of VEGFR2 (unknown origin) after 1 hr by ADP-Glo reagent based luminescent assay	ic50	0.0005	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases expression, affects cotreatment, decreases expression	6
Resveratrol	decreases expression, increases expression, decreases activity, decreases reaction, increases secretion (+1 more)	5
Oxygen	increases phosphorylation, affects cotreatment, affects phosphorylation, affects reaction, increases expression	4
Tretinoin	affects cotreatment, increases expression, decreases expression, affects expression	4
bisphenol A	decreases expression, increases expression, increases secretion	3
Estradiol	increases secretion, decreases reaction, increases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases expression, increases abundance	3
methylmercuric chloride	decreases expression, increases expression	2
andrographolide	affects binding, affects cotreatment, decreases reaction, increases phosphorylation, decreases expression	2
epigallocatechin gallate	decreases expression	2
demethoxycurcumin	affects cotreatment, decreases reaction, increases phosphorylation, affects expression	2
cordycepin	affects cotreatment, decreases expression, decreases reaction, increases expression	2
perfluorooctane sulfonic acid	decreases reaction, increases expression, decreases expression	2
Semaxinib	decreases activity	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
belinostat	increases expression, affects cotreatment	2
ponatinib	decreases activity	2
apatinib	affects cotreatment, decreases expression	2
(+)-JQ1 compound	increases phosphorylation, decreases expression, decreases reaction	2
Sorafenib	affects cotreatment, decreases phosphorylation	2
Vorinostat	affects cotreatment, increases expression	2
Glyphosate	decreases reaction, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Curcumin	affects cotreatment, decreases reaction, increases phosphorylation, affects expression	2
Glucose	decreases reaction, affects cotreatment, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	decreases expression	2
caulerpin	decreases expression	1

ChEMBL screening assays

2687 unique, capped per target: 2594 binding, 64 functional, 27 admet, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3371133	Binding	Inhibition of VEGFR (unknown origin) using poly (Glu, Tyr) 4:1 substrate incubated for 30 mins by HTRF assay	Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents. — Eur J Med Chem
CHEMBL673896	Functional	Inhibition of VEGF-stimulated mitogenesis in human umbilical vein endothelial cells	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
CHEMBL3757356	ADMET	Inhibition of TEL-fused VEGFR2 (unknown origin) expressed in mouse BA/F3 cells assessed as cell growth inhibition	A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. — J Med Chem

Cellosaurus cell lines

206 cell lines: 204 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0336	Huh-7	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_2957	Huh-7D12	Cancer cell line	Male
CVCL_4W53	Huh7S1	Cancer cell line	Male
CVCL_7927	Huh-7.5	Cancer cell line	Male
CVCL_9V14	293/KDR	Transformed cell line	Female
CVCL_A0TI	Huh-7.5 Tet-On	Cancer cell line	Male
CVCL_A5AV	Huh7.93	Cancer cell line	Male
CVCL_B7TI	HUH7-R	Cancer cell line	Male
CVCL_B7TJ	HUH7-R-LUC	Cancer cell line	Male

Clinical trials (associated diseases)

599 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
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial