EPHB4

Summary

EPHB4 (EPH receptor B4, HGNC:3395) is a protein-coding gene on chromosome 7q22.1, encoding Ephrin type-B receptor 4 (P54760). Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. In precision oncology, EPHB4 EXPRESSION is associated with resistance to Bevacizumab in Colorectal Cancer (CIViC Level B).

Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development.

Source: NCBI Gene 2050 — RefSeq curated summary.

At a glance

• Gene–disease (curated): EPHB4-associated vascular malformation spectrum (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,107 total — 70 pathogenic, 53 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes — 46 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_004444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3395
Approved symbol	EPHB4
Name	EPH receptor B4
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Tyro11
Ensembl gene	ENSG00000196411
Ensembl biotype	protein_coding
OMIM	600011
Entrez	2050

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000358173, ENST00000360620, ENST00000467515, ENST00000477446, ENST00000478459, ENST00000487222, ENST00000489808, ENST00000492403, ENST00000492878, ENST00000616502, ENST00000856888, ENST00000856889, ENST00000856890, ENST00000856891, ENST00000856892, ENST00000856893, ENST00000922072, ENST00000922073, ENST00000922074, ENST00000922075, ENST00000922076, ENST00000971335, ENST00000971336

RefSeq mRNA: 1 — MANE Select: NM_004444 NM_004444

CCDS: CCDS5706

Canonical transcript exons

ENST00000358173 — 17 exons

Exon	Start	End
ENSE00001639386	100802565	100803590
ENSE00001868923	100826979	100827523
ENSE00003487439	100813919	100814021
ENSE00003488266	100812747	100812994
ENSE00003488366	100824203	100824273
ENSE00003498954	100822271	100822667
ENSE00003536241	100807365	100807580
ENSE00003544337	100806420	100806569
ENSE00003550897	100813095	100813208
ENSE00003571088	100813652	100813716
ENSE00003576857	100805166	100805321
ENSE00003600110	100805501	100805694
ENSE00003617412	100820141	100820296
ENSE00003674875	100818520	100818644
ENSE00003679434	100823644	100823931
ENSE00003687732	100819557	100819889
ENSE00003688620	100817192	100817357

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 96.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.4635 / max 129.2729, expressed in 1463 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85249	13.5498	1433
85246	0.7010	439
85247	0.5984	366
85248	0.4734	285
85245	0.1308	43
85244	0.0101	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	96.38	gold quality
type B pancreatic cell	CL:0000169	96.18	silver quality
body of uterus	UBERON:0009853	95.76	gold quality
right adrenal gland	UBERON:0001233	95.29	gold quality
right adrenal gland cortex	UBERON:0035827	95.20	gold quality
left adrenal gland	UBERON:0001234	95.00	gold quality
left adrenal gland cortex	UBERON:0035825	95.00	gold quality
right lung	UBERON:0002167	94.86	gold quality
adrenal cortex	UBERON:0001235	94.57	gold quality
ectocervix	UBERON:0012249	94.28	gold quality
adrenal gland	UBERON:0002369	94.24	gold quality
endometrium epithelium	UBERON:0004811	93.92	gold quality
endocervix	UBERON:0000458	93.89	gold quality
adrenal tissue	UBERON:0018303	93.78	gold quality
pancreatic ductal cell	CL:0002079	93.51	silver quality
myometrium	UBERON:0001296	93.22	gold quality
left ovary	UBERON:0002119	93.16	gold quality
stromal cell of endometrium	CL:0002255	93.09	gold quality
right ovary	UBERON:0002118	93.00	gold quality
spleen	UBERON:0002106	92.76	gold quality
gall bladder	UBERON:0002110	92.43	gold quality
vena cava	UBERON:0004087	92.39	silver quality
skin of abdomen	UBERON:0001416	92.18	gold quality
apex of heart	UBERON:0002098	92.11	gold quality
placenta	UBERON:0001987	92.09	gold quality
skin of leg	UBERON:0001511	91.94	gold quality
tongue squamous epithelium	UBERON:0006919	91.87	silver quality
metanephros cortex	UBERON:0010533	91.86	gold quality
left uterine tube	UBERON:0001303	91.85	gold quality
upper lobe of left lung	UBERON:0008952	91.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, GATA5, HOXA9, RBPJ, TCF3, TP53, YBX3

miRNA regulators (miRDB)

83 targeting EPHB4, 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-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-9-5P	100.00	72.28	2361
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587

Literature-anchored findings (GeneRIF, showing 40)

• accelerates differentiation of select human hematopoietic cells (PMID:11929761)
• role of EphB4 receptor in erythropoiesis (PMID:12051776)
• Eph B4 stimulates migration and proliferation and may play a role in angiogenesis (PMID:12235151)
• EphB4 is pro-adhesive and stimulates endothelial cell migration and sprouting angiogenesis. EphrinB2-mediated repulsive signals are transduced by EphB4. (PMID:12734395)
• HoxA9 binds to the EphB4 promoter & stimulates its expression resulting in an increase of endothelial cell migration and tube forming activity. Thus, modulation of EphB4 expression may contribute to the proangiogenic effect of HoxA9 in endothelial cells. (PMID:14764452)
• in hyperinflammatory lesions, ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules; syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells after stimulation with preclustered ephrinB2 (PMID:15126321)
• EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were expressed in the placenta (PMID:15193868)
• These results suggest that activation of EphB4 participates in adhesive but not repulsive signals independently of its tyrosine kinase activity in hematopoietic cells. (PMID:15358160)
• analysis of EphB1, EphB2, and EphB4-binding peptides interaction with antagonists with ephrin-like affinity (PMID:15722342)
• EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. (PMID:15930280)
• EPHB4 regulates chemokine-evoked trophoblast responses: a mechanism for incorporating the human placenta into the maternal circulation. (PMID:16107476)
• EphB4 is expressed in prostate cancer cell lines with increased expression in human prostate cancers when compared with matched normal tissue (PMID:16171530)
• EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature (PMID:16205642)
• EphB4 and ephrin-B2 are instrumental in the establishment of a functional placental structure and of the utero-placental circulation. (PMID:16343615)
• EphB4 acts as a negative regulator of blood vessel branching and vascular network formation, switching the vascularization program from sprouting angiogenesis to circumferential vessel growth. (PMID:16424904)
• Overexpression of EphB4 is associated with squamous cell carcinoma of the head and neck (PMID:16615113)
• novel link between EphB forward signaling and SDF-1-induced signaling demonstrates a mechanism for cooperative regulation of endothelial cell movement. (PMID:16840724)
• The results provide critical information on the EphB4*ephrinB2 protein interfaces and their mode of interaction, which will facilitate development of small molecule compounds inhibiting the EphB4*ephrinB2 interaction as novel cancer therapeutics. (PMID:16867992)
• Study provides evidence showing that promoter methylation regulates EPHB4 transcription and that EPHB4 can regulate the long-term clonogenic potential of colorectal tumor cells, revealing EPHB4 as a potential tumor suppressor gene in colorectal cancer. (PMID:16982731)
• demonstrates that Eph B4 and Ephrin B2 interaction may play an important role in the oncogenesis and angiogenesis of cervical carcinomas (PMID:17196593)
• Notch signaling by induction of Dll1 was necessary & sufficient to induce EphB4-dependent branching morphogenesis in human arterial EC. (PMID:17234965)
• Overexpression of EphB4 is associated with ovarian cancer (PMID:17353927)
• activation of EphB4 enhances proangiogenic capacity through induction of PSGL-1 expression and adhesion to E selectin and P selectin (PMID:17510705)
• EphB4 expression was found in 44 (72.1%) out of 61 cancer tissues analysed. (PMID:17611172)
• Overexpression of EphB4 is associated with tumour advancement of ovarian cancers (PMID:18231102)
• EphB4 is a critical component of the CYP2C9- and 11,12-EET-activated signaling cascade that promotes angiogenesis in vitro as well as in vivo. (PMID:18340006)
• EphBR-ephrinB interactions lead to monocyte adhesion and transmigration through the vascular endothelium. (PMID:18957513)
• EphB4 receptor activation by ephrin B2 in osteoarthritis subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities (PMID:19035475)
• High EphB4 is associated with malignant urogenital tissue. (PMID:19272799)
• Localization of EphB4 is dominantly in the cancer cells of uterine cervical cancers of all cases given. (PMID:19356789)
• EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. (PMID:19366806)
• The findings demonstrate that EphB4 can affect cancer cell behaviour in an ephrin-independent manner. (PMID:19552627)
• the ephrinB2/EphB4 axis is dysregulated in multiple myeloma, and its activation by EphB4-Fc inhibits myeloma growth and bone disease (PMID:19597185)
• Our study is the first to provide data on the presence and role of ephrin B2/EphB4 receptors in human chondrocytes/cartilage (PMID:19664212)
• EphB4 mediates a new mechanism of imatinib resistance that is independent of BCR-ABL and dependent on the RAS/MAPK pathway. (PMID:20002159)
• EPHB4 gene polymorphisms are associated with the risk of intracranial hemorrhage in patients with brain arteriovenous malformations. (PMID:20031623)
• EPHB4 can function as a tumor suppressor in acute lymphoblastic leukemia (PMID:20061560)
• MAb47 targets fibronectin-like domain 2 of both human and murine EphB4 and does not alter EphB4 receptor levels, but inhibits angiogenesis and growth of both EphB4-positive and EphB4-negative tumors in a mouse s.c. xenograft model (PMID:20133814)
• Ephb4 was over-expressed and localized to the cytoplasm of gastric cancer cells. Moreover, Ephb4 protein was observed as being significantly related to tumor size and regional lymph nodes category. (PMID:20686847)
• EphB4/ephrinB2 interactions between tumor cells and endothelial cells identify a mechanism for site-specific metastatic dissemination of tumor cells. (PMID:21047731)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ephb4b	ENSDARG00000027112
mus_musculus	Ephb4	ENSMUSG00000029710
rattus_norvegicus	Ephb4	ENSRNOG00000045952

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), 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)

Protein

Protein identifiers

Ephrin type-B receptor 4 — P54760 (reviewed: P54760)

Alternative names: Hepatoma transmembrane kinase, Tyrosine-protein kinase TYRO11

All UniProt accessions (3): P54760, Q541P7, Q96L35

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells.

Subunit / interactions. Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts with RASA1; the interaction depends on EPHB4 tyrosine-phosphorylation.

Subcellular location. Cell membrane.

Tissue specificity. Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix.

Post-translational modifications. Phosphorylated; autophosphorylation is stimulated by EFNB2.

Disease relevance. Lymphatic malformation 7 (LMPHM7) [MIM:617300] 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. LMPHM7 is an autosomal dominant form with variable expressivity. Some individuals present with severe non-immune hydrops fetalis, which may cause perinatal demise or fully resolve after the neonatal period. Others present with no edema and have milder clinical features, such as atrial septal defect or varicose veins as adults. The disease is caused by variants affecting the gene represented in this entry. Capillary malformation-arteriovenous malformation 2 (CMAVM2) [MIM:618196] An autosomal dominant disorder characterized by multiple, round to oval or more irregularly shaped macules that are pinkish red in color and are randomly distributed across the body. These capillary malformations are associated with either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P54760-1	1	yes
P54760-2	2
P54760-3	3
P54760-4	4

RefSeq proteins (1): NP_004435* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001090	EPH_LBD	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001426	Tyr_kinase_rcpt_V_CS	Conserved_site
IPR001660	SAM	Domain
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011641	Tyr-kin_ephrin_A/B_rcpt-like	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016257	EPH	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR027936	EPH_TM	Domain
IPR034290	EphB4_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR037636	EPH-B4_SAM	Domain
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF00536, PF01404, PF07699, PF07714, PF14575, PF25599

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 (144 total): sequence variant 49, strand 30, helix 22, modified residue 6, splice variant 6, turn 5, domain 5, sequence conflict 4, glycosylation site 3, binding site 2, topological domain 2, disulfide bond 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, active site 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
6FNK	X-RAY DIFFRACTION	1.05
6FNM	X-RAY DIFFRACTION	1.16
6FNJ	X-RAY DIFFRACTION	1.24
6FNL	X-RAY DIFFRACTION	1.27
6FNI	X-RAY DIFFRACTION	1.47
2BBA	X-RAY DIFFRACTION	1.65
2VWX	X-RAY DIFFRACTION	1.65
2VWY	X-RAY DIFFRACTION	1.65
2VWZ	X-RAY DIFFRACTION	1.65
2VX1	X-RAY DIFFRACTION	1.65
4BB4	X-RAY DIFFRACTION	1.65
2XVD	X-RAY DIFFRACTION	1.7
2X9F	X-RAY DIFFRACTION	1.75
2VWV	X-RAY DIFFRACTION	1.9
2VWW	X-RAY DIFFRACTION	1.9
2VWU	X-RAY DIFFRACTION	2
2HLE	X-RAY DIFFRACTION	2.05
2QKQ	X-RAY DIFFRACTION	2.1
2VX0	X-RAY DIFFRACTION	2.1
2YN8	X-RAY DIFFRACTION	2.11
4AW5	X-RAY DIFFRACTION	2.33
3ZEW	X-RAY DIFFRACTION	2.5
2E7H	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54760-F1	82.46	0.48

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): 740 (proton acceptor)

Ligand- & substrate-binding residues (2): 621–629; 647

Post-translational modifications (6): 769, 770, 911, 943, 976, 987

Disulfide bonds (2): 61–184, 97–107

Glycosylation sites (3): 203, 335, 426

Mutagenesis-validated functional residues (1):

Position	Phenotype
95	reduces binding affinity for efnb2.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 241 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, MAHAJAN_RESPONSE_TO_IL1A_DN, GOBP_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_SPROUTING_ANGIOGENESIS, AMIT_EGF_RESPONSE_120_HELA, GOBP_HEART_MORPHOGENESIS, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_EPHRIN_RECEPTOR_SIGNALING_PATHWAY, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, GOMF_TRANSMEMBRANE_RECEPTOR_PROTEIN_KINASE_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TIEN_INTESTINE_PROBIOTICS_2HR_UP

GO Biological Process (7): angiogenesis (GO:0001525), cell migration involved in sprouting angiogenesis (GO:0002042), heart morphogenesis (GO:0003007), cell adhesion (GO:0007155), ephrin receptor signaling pathway (GO:0048013), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169)

GO Molecular Function (9): transmembrane receptor protein tyrosine kinase activity (GO:0004714), ephrin receptor activity (GO:0005003), ATP binding (GO:0005524), 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)

GO Cellular Component (6): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	3
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
heart development	1
animal organ morphogenesis	1
cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
transmembrane receptor protein tyrosine kinase activity	1
ephrin receptor signaling pathway	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein kinase activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1
protein-containing complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

2210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHB4	EFNB2	P52799	999
EPHB4	EFNB1	P98172	994
EPHB4	EFNB3	Q15768	968
EPHB4	EFNA5	P52803	773
EPHB4	VEGFC	P49767	763
EPHB4	EPO	P01588	761
EPHB4	HEY2	Q9UBP5	752
EPHB4	EFNA2	O43921	747
EPHB4	EFNA1	P20827	741
EPHB4	EFNA4	P52798	728
EPHB4	CRK	P46108	715
EPHB4	EFNA3	P52797	708
EPHB4	EPHB2	P29323	694
EPHB4	BCAR1	P56945	685
EPHB4	RASA1	P20936	641

IntAct

141 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
EPHB4	EFNB2	psi-mi:“MI:0407”(direct interaction)	0.830
FKBP5	IKBKB	psi-mi:“MI:0914”(association)	0.640
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
EPO	EPHB4	psi-mi:“MI:0407”(direct interaction)	0.540
EPHB4	EPO	psi-mi:“MI:0407”(direct interaction)	0.540
EPO	EPHB4	psi-mi:“MI:0915”(physical association)	0.540
EPHB4	EPO	psi-mi:“MI:0915”(physical association)	0.540
EPHA7	EPHB4	psi-mi:“MI:0915”(physical association)	0.540
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
GABRE	FZD6	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
NRROS	NDUFA3	psi-mi:“MI:0914”(association)	0.530
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
SLC9A8	ZNF432	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
EGFR	XPOT	psi-mi:“MI:0914”(association)	0.530

BioGRID (196): EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Proximity Label-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RPR8, O02740, O08644, O09127, O15197, O19179, O73875, O73878, P0C0K6, P0C0K7, P14616, P16067, P20594, P21709, P26770, P29317, P29322, P35590, P46197, P51839, P51840, P51841, P51842, P52333, P52785, P54753, P54754, P54760, P54761, P55203, P55205, Q02846, Q03146, Q06805, Q06806, Q08345, Q1KL86, Q5JZY3, Q5SDA5, Q60750

Diamond homologs: A0JNB0, A1Y2K1, A2VDU3, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, F4JTP5, H2KZW3, O01700, O08680, O13146, O13148, O22558, O42422, O43283, O43318, O73878, P00523, P00524, P00525, P00526, P05480, P09759, P0C8E4, P12931, P13115, P13116, P13406, P14085, P15054, P15209, P21709, P27446, P28693, P29318, P29319, P29320, P29323

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	down-regulates	EPHB4	“chemical inhibition”
EPHB4	“up-regulates activity”	NOS3	phosphorylation
EFNB1	up-regulates	EPHB4	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1107 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	70
Likely pathogenic	53
Uncertain significance	433
Likely benign	369
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172836	NM_004444.5(EPHB4):c.2600T>C (p.Phe867Ser)	Pathogenic
1383632	NM_004444.5(EPHB4):c.235_236del (p.Pro79fs)	Pathogenic
1421631	NM_004444.5(EPHB4):c.190C>T (p.Gln64Ter)	Pathogenic
1426188	NM_004444.5(EPHB4):c.1039dup (p.Leu347fs)	Pathogenic
1451586	NM_004444.5(EPHB4):c.946dup (p.Arg316fs)	Pathogenic
1452020	NM_004444.5(EPHB4):c.1960_1964del (p.Thr654fs)	Pathogenic
1454230	NM_004444.5(EPHB4):c.693del (p.Gly232fs)	Pathogenic
1455974	NC_000007.13:g.(?100411521)(100424652_?)del	Pathogenic
1456371	NM_004444.5(EPHB4):c.582C>A (p.Tyr194Ter)	Pathogenic
1458604	NM_004444.5(EPHB4):c.1291C>T (p.Arg431Ter)	Pathogenic
1459131	NM_004444.5(EPHB4):c.174C>A (p.Tyr58Ter)	Pathogenic
1527379	GRCh37/hg19 7q22.1-31.1(chr7:99417471-111586308)	Pathogenic
1691322	NM_004444.5(EPHB4):c.121C>T (p.Gln41Ter)	Pathogenic
1700049	NM_004444.5(EPHB4):c.2011T>C (p.Phe671Leu)	Pathogenic
1704386	NM_004444.5(EPHB4):c.2215C>T (p.Arg739Ter)	Pathogenic
1751992	NM_004444.5(EPHB4):c.616C>T (p.Arg206Ter)	Pathogenic
1756739	NM_004444.5(EPHB4):c.1236_1237insGCCTCCTTAGCCACGGGGCA (p.Ser413fs)	Pathogenic
1790636	NM_004444.5(EPHB4):c.2397del (p.Ala800fs)	Pathogenic
1806103	NM_004444.5(EPHB4):c.1788T>A (p.Tyr596Ter)	Pathogenic
1806264	NM_004444.5(EPHB4):c.216G>A (p.Trp72Ter)	Pathogenic
1961827	NM_004444.5(EPHB4):c.96G>A (p.Trp32Ter)	Pathogenic
2011806	NM_004444.5(EPHB4):c.1428_1447dup (p.Arg483fs)	Pathogenic
2019271	NM_004444.5(EPHB4):c.2078_2079del (p.Thr693fs)	Pathogenic
2020695	NM_004444.5(EPHB4):c.1548del (p.Phe518fs)	Pathogenic
2021724	NM_004444.5(EPHB4):c.449dup (p.Gly152fs)	Pathogenic
2425116	NC_000007.13:g.(?100410349)(100424652_?)del	Pathogenic
2446205	NM_004444.5(EPHB4):c.2022dup (p.Asn675fs)	Pathogenic
2630732	NM_004444.5(EPHB4):c.924C>G (p.Tyr308Ter)	Pathogenic
2694538	NM_004444.5(EPHB4):c.844G>T (p.Glu282Ter)	Pathogenic
2704988	NM_004444.5(EPHB4):c.589T>G (p.Cys197Gly)	Pathogenic

SpliceAI

2643 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100803586:GGTCC:G	acceptor_gain	1.0000
7:100803587:GTCC:G	acceptor_gain	1.0000
7:100803588:TCC:T	acceptor_gain	1.0000
7:100803589:CC:C	acceptor_gain	1.0000
7:100803589:CCC:C	acceptor_gain	1.0000
7:100803590:CC:C	acceptor_gain	1.0000
7:100803590:CCTGC:C	acceptor_loss	1.0000
7:100803591:C:CC	acceptor_gain	1.0000
7:100803592:T:G	acceptor_loss	1.0000
7:100803594:C:CT	acceptor_gain	1.0000
7:100805161:CTTA:C	donor_loss	1.0000
7:100805162:TTACT:T	donor_loss	1.0000
7:100805163:TACT:T	donor_loss	1.0000
7:100805164:A:AC	donor_gain	1.0000
7:100805165:C:CA	donor_gain	1.0000
7:100805165:CT:C	donor_gain	1.0000
7:100805165:CTCAG:C	donor_gain	1.0000
7:100805169:G:C	donor_gain	1.0000
7:100805320:CC:C	acceptor_gain	1.0000
7:100805321:CC:C	acceptor_gain	1.0000
7:100805322:C:CC	acceptor_gain	1.0000
7:100805323:T:C	acceptor_loss	1.0000
7:100805495:CCTCA:C	donor_loss	1.0000
7:100805496:CTCA:C	donor_loss	1.0000
7:100805497:TCA:T	donor_loss	1.0000
7:100805498:CA:C	donor_loss	1.0000
7:100805499:A:AC	donor_gain	1.0000
7:100805499:A:AG	donor_loss	1.0000
7:100805499:AC:A	donor_gain	1.0000
7:100805499:ACCCG:A	donor_gain	1.0000

AlphaMissense

6350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100805253:A:G	L916P	1.000
7:100805253:A:T	L916H	1.000
7:100805257:A:G	W915R	1.000
7:100805257:A:T	W915R	1.000
7:100805558:A:G	L874P	1.000
7:100805608:C:A	W857C	1.000
7:100805608:C:G	W857C	1.000
7:100805610:A:G	W857R	1.000
7:100805610:A:T	W857R	1.000
7:100805613:A:G	C856R	1.000
7:100805624:A:G	L852P	1.000
7:100805646:A:G	C845R	1.000
7:100805663:A:T	L839Q	1.000
7:100805685:C:G	A832P	1.000
7:100806426:A:C	N826K	1.000
7:100806426:A:T	N826K	1.000
7:100806438:C:A	W822C	1.000
7:100806438:C:G	W822C	1.000
7:100806440:A:G	W822R	1.000
7:100806440:A:T	W822R	1.000
7:100806443:A:C	Y821D	1.000
7:100806443:A:G	Y821H	1.000
7:100806445:G:T	P820Q	1.000
7:100806454:C:A	G817V	1.000
7:100806454:C:T	G817E	1.000
7:100806455:C:A	G817W	1.000
7:100806469:T:A	E812V	1.000
7:100806470:C:T	E812K	1.000
7:100806471:C:A	W811C	1.000
7:100806471:C:G	W811C	1.000

dbSNP variants (sampled 300 via entrez): RS1000064371 (7:100809550 A>G), RS1000225657 (7:100824929 G>A), RS1000273764 (7:100819886 G>C), RS1000512467 (7:100818985 C>G,T), RS1000717909 (7:100825598 C>A,T), RS1000936131 (7:100811726 T>C,G), RS1000968555 (7:100811538 C>G), RS1001021630 (7:100813983 C>T), RS1001069217 (7:100814296 T>TG), RS1001088125 (7:100825445 T>G), RS1001123214 (7:100816881 A>C), RS1001170707 (7:100806534 C>A,G), RS1001308727 (7:100812672 G>A), RS1001493373 (7:100817701 C>G,T), RS1001554634 (7:100816756 G>A)

Disease associations

OMIM: gene MIM:600011 | disease phenotypes: MIM:617300, MIM:618196, MIM:608354, MIM:153100, MIM:187500, MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
EPHB4-associated vascular malformation spectrum	Definitive	Autosomal dominant
capillary malformation-arteriovenous malformation 2	Definitive	Autosomal dominant
lymphatic malformation 7	Strong	Autosomal dominant
capillary malformation-arteriovenous malformation syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
EPHB4-associated vascular malformation spectrum	Definitive	AD

Mondo (10): lymphatic malformation 7 (MONDO:0015009), capillary malformation-arteriovenous malformation 2 (MONDO:0020785), vein of Galen aneurysm (MONDO:0015196), capillary malformation-arteriovenous malformation syndrome (MONDO:0012016), lymphatic malformation 1 (MONDO:0007919), lymphedema (MONDO:0019297), tetralogy of fallot (MONDO:0008542), EPHB4-associated vascular malformation spectrum (MONDO:0700080), non-immune hydrops fetalis (MONDO:0009369), cancer (MONDO:0004992)

Orphanet (7): EPHB4-related capillary malformation-arteriovenous malformation (Orphanet:693912), Vein of Galen malformation (Orphanet:1053), Capillary malformation-arteriovenous malformation (Orphanet:137667), Milroy disease (Orphanet:79452), Tetralogy of Fallot (Orphanet:3303), Non-immune hydrops fetalis (Orphanet:363999), OBSOLETE: Lymphedema (Orphanet:79383)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000282	Facial edema
HP:0000969	Edema
HP:0000987	Atypical scarring of skin
HP:0001004	Lymphedema
HP:0001009	Telangiectasia
HP:0001541	Ascites
HP:0001581	Recurrent skin infections
HP:0001631	Atrial septal defect
HP:0001698	Pericardial effusion
HP:0001790	Nonimmune hydrops fetalis
HP:0001903	Anemia
HP:0002098	Respiratory distress
HP:0002202	Pleural effusion
HP:0002617	Vascular dilatation
HP:0002619	Varicose veins
HP:0002732	Lymph node hypoplasia
HP:0002849	Absence of lymph node germinal center
HP:0003270	Abdominal distention
HP:0003550	Predominantly lower limb lymphedema
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003829	Typified by incomplete penetrance
HP:0005406	Recurrent bacterial skin infections
HP:0007514	Edema of the dorsum of hands
HP:0010310	Chylothorax
HP:0010741	Pedal edema
HP:0010781	Skin dimple
HP:0010880	Increased nuchal translucency
HP:0012027	Laryngeal edema

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001684_4	Plasminogen activator inhibitor type 1 levels (PAI-1)	6.000000e-13
GCST003818_36	Resting heart rate	1.000000e-41
GCST004602_59	Mean corpuscular volume	3.000000e-15
GCST004630_263	Mean corpuscular hemoglobin	1.000000e-23
GCST006988_67	Blond vs. brown/black hair color	8.000000e-12
GCST008103_164	Bipolar disorder	7.000000e-06
GCST011939_12	Takayasu arteritis	9.000000e-06
GCST90002401_462	Platelet distribution width	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004792	plasminogen activator inhibitor 1 measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0003924	hair color
EFO:0007984	platelet component distribution width

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008209	Lymphedema	C15.604.496
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C564254	Capillary Malformation-Arteriovenous Malformation (supp.)
C536535	Vein of Galen aneurysm (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL4523737 (PROTEIN-PROTEIN INTERACTION), CHEMBL5147 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

46 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 601,079 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4	117,814
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3544983	TESEVATINIB	3	2,819
CHEMBL3545154	POZIOTINIB	3	1,560
CHEMBL483158	ALISERTIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL119385	NEFLAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL1738757	REBASTINIB	2
CHEMBL2029988	CEP-32496	2
CHEMBL206834	BAFETINIB	2
CHEMBL2408045	SAPITINIB	2

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
EPHB4 EXPRESSION	Bevacizumab	Colorectal Cancer	Resistance	CIViC B	EID905

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type XIII RTKs: Ephrin receptor family

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
tesevatinib	Inhibition	8.85	pIC50
compound 66 [PMID: 19788238]	Inhibition	8.8	pIC50
NVP-BHG712	Inhibition	8.22	pKd
NVP-BHG712 isomer	Inhibition	6.85	pKd
compound 20 [PMID: 23489211]	Inhibition	5.36	pIC50

Binding affinities (BindingDB)

305 measured of 458 human assays (462 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
MLS000103371	EC50	0.00942 nM
2,2-diketo-6-phenyl-3,4-dihydrothiazolo[2,3-c][1,2,4]thiadiazine-7-carboxylic acid ethyl ester	EC50	0.00961 nM
tert-butyl 4-amino-3-[2-[2-methyl-5-[[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]phenyl]ethynyl]pyrazolo[3,4-d]pyrimidine-1-carboxylate	IC50	11 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	IC50	15.9 nM	US-8481536: Benzotriazine inhibitors of kinases
N-[3-[2-[4-amino-1-(1-methylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	18 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
BMS-354825	KD	27 nM
4-[[7-(2-chloro-5-hydroxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide	IC50	30.8 nM	US-8481536: Benzotriazine inhibitors of kinases
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide	IC50	33 nM
3-({4-[(5-chloro-2H-1,3-benzodioxol-4-yl)amino]pyrimidin-2-yl}amino)benzene-1-sulfonamide	IC50	40 nM
7-(2,6-dichlorophenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amine	IC50	40 nM	US-8481536: Benzotriazine inhibitors of kinases
1-cyclobutyl-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, PP494	IC50	47 nM
N-[4-(2-cyclopentylethoxy)phenyl]-7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-amine	IC50	49 nM	US-8481536: Benzotriazine inhibitors of kinases
1-cyclopentyl-3-(H-imidazo[1,2-a]pyridin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, PP162	IC50	53 nM
7-(2-chlorophenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amine	IC50	58 nM	US-8481536: Benzotriazine inhibitors of kinases
1-(1-adamantyl)-3-[3-(2-ketopyrrolidino)propyl]urea	IC50	65.6 nM
[4-[[7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]phenyl]-(4-methylpiperazin-1-yl)methanone	IC50	66 nM	US-8481536: Benzotriazine inhibitors of kinases
2-[[7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)-1,3-thiazole-4-carboxamide	IC50	66.1 nM	US-8481536: Benzotriazine inhibitors of kinases
5-[[7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)furan-2-carboxamide	IC50	68.7 nM	US-8481536: Benzotriazine inhibitors of kinases
4-[[7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide	IC50	73.7 nM	US-8481536: Benzotriazine inhibitors of kinases
4-N-(5-chloro-2H-1,3-benzodioxol-4-yl)-2-N-(3-methanesulfonylphenyl)pyrimidine-2,4-diamine	IC50	90 nM
7-(2,6-dimethylphenyl)-5-methyl-N-[2-(2-pyrrolidin-1-ylethoxy)-4-pyridinyl]-1,2,4-benzotriazin-3-amine	IC50	128 nM	US-8481536: Benzotriazine inhibitors of kinases
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
4-N-(5-chloro-2H-1,3-benzodioxol-4-yl)-2-N-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine	IC50	240 nM
4-({4-[(5-chloro-2H-1,3-benzodioxol-4-yl)amino]pyrimidin-2-yl}amino)benzene-1-sulfonamide	IC50	300 nM
4-[[7-[2,6-bis(fluoranyl)phenyl]-9-chloranyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	KD	300 nM
BMCL182776 Compound 1	IC50	350 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
5-methyl-7-phenyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amine	IC50	391 nM	US-8481536: Benzotriazine inhibitors of kinases
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM
4-N-(5-chloro-2H-1,3-benzodioxol-4-yl)-2-N-(3-methylphenyl)pyrimidine-2,4-diamine	IC50	460 nM
N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3aR,5r,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-7- ({[(3aR,5r,6aS)-2- ethyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-6- (methyloxy)-7-({[(3aR,5r,6aS)-2-(2- methylpropyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-2,3-dichlorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)- hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin- 3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-5-chloro-2-fluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)- hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin- 3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-5-chloro-2-fluorophenyl)-7- {[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)- hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin- 3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)- hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)- hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,8aS)- hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-7- ({[(3aR,5r,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
7-({[(3aR,5r,6aS)-2- acetyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-N-(4-bromo-3-chloro-2- fluorophenyl)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-6- (methyloxy)-7-{[(3aR,5r,6aS)- octahydrocyclopenta[c]pyrrol-5- ylmethyl]oxy}quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
ethyl (3aR,6aS)-5-[[4-(4-bromo-3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxymethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(4-bromo-3-chloro-2-fluorophenyl)-6- (methyloxy)-7-({[(3aR,5r,6aS)-2- (methylsulfonyl)octahydrocyclopenta[c]pyrrol- 5-yl]methyl}oxy)quinazolin-4-amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors
N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3aR,5r,6aS)-2- ethyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine	IC50	525 nM	US-9796704: Substituted quinazolines as receptor-type kinase inhibitors

ChEMBL bioactivities

1057 potent at pChembl≥5 of 1179 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.89	IC50	0.13	nM	CHEMBL4100979
9.80	IC50	0.16	nM	CHEMBL4469077
9.70	IC50	0.2	nM	SORAFENIB
9.66	IC50	0.22	nM	SORAFENIB
9.60	IC50	0.25	nM	CHEMBL4459732
9.57	IC50	0.27	nM	CHEMBL4069517
9.49	IC50	0.32	nM	CHEMBL4456738
9.47	Kd	0.34	nM	DASATINIB
9.40	IC50	0.4	nM	CHEMBL241682
9.36	IC50	0.44	nM	CHEMBL4519953
9.05	Kd	0.9	nM	CHEMBL400402
9.05	IC50	0.9	nM	CHEMBL1270280
9.00	IC50	1	nM	CHEMBL496760
8.90	IC50	1.26	nM	CHEMBL4101918
8.89	IC50	1.3	nM	CHEMBL1269858
8.83	IC50	1.49	nM	CHEMBL4453627
8.80	IC50	1.6	nM	CHEMBL566515
8.70	Kd	2	nM	CHEMBL4291811
8.70	IC50	2	nM	CHEMBL497198
8.70	IC50	2	nM	CHEMBL523744
8.70	IC50	2	nM	CHEMBL468970
8.70	IC50	2	nM	CHEMBL1738764
8.70	IC50	2	nM	CHEMBL1762535
8.70	IC50	2	nM	CHEMBL1762531
8.70	IC50	2	nM	CHEMBL1762529
8.70	IC50	2	nM	CHEMBL1762525
8.68	IC50	2.07	nM	DASATINIB ANHYDROUS
8.67	IC50	2.13	nM	CHEMBL4543212
8.66	IC50	2.21	nM	CHEMBL4525897
8.59	IC50	2.6	nM	CHEMBL1270378
8.52	IC50	2.99	nM	CHEMBL4441465
8.52	IC50	3	nM	CHEMBL3752910
8.52	IC50	3	nM	CHEMBL1762546
8.48	IC50	3.3	nM	CHEMBL4452405
8.44	IC50	3.6	nM	CHEMBL4071731
8.43	Kd	3.7	nM	DASATINIB ANHYDROUS
8.43	Kd	3.681	nM	DASATINIB ANHYDROUS
8.41	IC50	3.87	nM	CHEMBL4171543
8.40	Kd	4	nM	DASATINIB
8.40	EC50	4	nM	CHEMBL459850
8.40	IC50	4	nM	CHEMBL468970
8.40	IC50	4	nM	CHEMBL1762547
8.40	IC50	4	nM	CHEMBL1762539
8.40	IC50	4	nM	CHEMBL1762530
8.35	IC50	4.46	nM	SORAFENIB
8.34	IC50	4.53	nM	CHEMBL4104599
8.34	IC50	4.62	nM	SORAFENIB
8.33	IC50	4.71	nM	CHEMBL4160854
8.30	IC50	5	nM	CHEMBL566515
8.30	IC50	5	nM	CHEMBL3787112

PubChem BioAssay actives

660 with measured affinity, of 2116 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-N-[4-(3-amino-1H-indazol-4-yl)phenyl]-1-N’-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0001	uM
4-(2-fluorophenyl)-1-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]triazole	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0002	uM
Sorafenib	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0002	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	435404: Binding constant for EPHB4 kinase domain	kd	0.0003	uM
1-[4-(2-aminoquinazolin-7-yl)phenyl]-3-[3-bromo-5-(trifluoromethyl)phenyl]thiourea	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0003	uM
5-[4-[(4-phenyltriazol-1-yl)methyl]phenyl]pyrimidine	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0003	uM
5-[4-[[4-(2-fluorophenyl)triazol-1-yl]methyl]phenyl]pyrimidine	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0003	uM
3-[4-[[4-(4-methylphenyl)triazol-1-yl]methyl]phenyl]pyridine	1533551: Inhibition of EPHB4 (unknown origin) after 4 hrs by ADP-Glo reagent based luminescent assay	ic50	0.0004	uM
1-[4-[4-amino-7-(3-sulfamoylphenyl)furo[3,2-c]pyridin-3-yl]phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea	304934: Inhibition of human EphB4 by scintillation proximity method	ic50	0.0004	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1424994: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0009	uM
2-N-(2,6-dimorpholin-4-yl-4-pyridinyl)-4-N-(1H-indazol-4-yl)-4-N-methylpyrimidine-2,4-diamine	526273: Inhibition of EphB4 by acoustic dispensing assay	ic50	0.0009	uM
3-[[4-[(5-chloro-1,3-benzodioxol-4-yl)amino]pyrimidin-2-yl]amino]-5-(methanesulfonamido)benzenesulfonamide	349242: Inhibition of EphB4	ic50	0.0010	uM
1-N-[4-(3-amino-1H-indazol-4-yl)phenyl]-1-N’-(1,3-benzodioxol-5-yl)cyclopropane-1,1-dicarboxamide	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0013	uM
2-N-(3,5-dimorpholin-4-ylphenyl)-4-N-(1H-indazol-4-yl)-4-N-methylpyrimidine-2,4-diamine	526273: Inhibition of EphB4 by acoustic dispensing assay	ic50	0.0013	uM
1-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-4-phenyltriazole	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0015	uM
7-(5-hydroxy-2-methylphenyl)-6-(2-methoxyphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione	441383: Inhibition of EphB4 by [gamma33-P]ATP based assay	ic50	0.0016	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-1-[2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-4-oxobutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxypropanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-3-methylpentanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1424426: Binding affinity to Fc-tagged EphB4 (unknown origin) assessed as reduction in ephrin-B2 binding by SPR assay	kd	0.0020	uM
[4-methyl-3-[[2-(3-methylsulfonyl-5-morpholin-4-ylanilino)pyrimidin-4-yl]-propan-2-ylamino]phenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0020	uM
2-N-(3,5-dimorpholin-4-ylphenyl)-4-N-(3-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine	591196: Inhibition of human EPHB4	ic50	0.0020	uM
[2-chloro-5-[[2-(3,5-dimorpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]phenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0020	uM
[3-[[2-(3,5-dimorpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]-5-methoxyphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0020	uM
4-N-(5-chloro-1,3-benzodioxol-4-yl)-2-N-(3,5-dimorpholin-4-ylphenyl)pyrimidine-2,4-diamine	349242: Inhibition of EphB4	ic50	0.0020	uM
2-N-(3,5-dimorpholin-4-ylphenyl)-4-N-(5-methoxy-3-pyridinyl)-4-N-methylpyrimidine-2,4-diamine	591196: Inhibition of human EPHB4	ic50	0.0020	uM
4-N-(5-chloro-1,3-benzodioxol-4-yl)-2-N-(3-methylsulfonyl-5-morpholin-4-ylphenyl)pyrimidine-2,4-diamine	349242: Inhibition of EphB4	ic50	0.0020	uM
N-[3-[[4-[(5-chloro-1,3-benzodioxol-4-yl)amino]pyrimidin-2-yl]amino]-5-morpholin-4-ylphenyl]methanesulfonamide	349242: Inhibition of EphB4	ic50	0.0020	uM
4-(4-methylphenyl)-1-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]triazole	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0021	uM
Dasatinib	2147749: Inhibition of Nano Luc-fused full length C-terminal EPHB4 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0021	uM
1-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-4-[4-(trifluoromethyl)phenyl]triazole	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0022	uM
2-N-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-N-(1H-indazol-4-yl)-4-N-methylpyrimidine-2,4-diamine	526273: Inhibition of EphB4 by acoustic dispensing assay	ic50	0.0026	uM
3-[1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]triazol-4-yl]aniline	1533551: Inhibition of EPHB4 (unknown origin) after 4 hrs by ADP-Glo reagent based luminescent assay	ic50	0.0030	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147749: Inhibition of Nano Luc-fused full length C-terminal EPHB4 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0030	uM
[4-methyl-3-[methyl-[2-(3-methylsulfonyl-5-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0030	uM
5-[4-[[4-(4-methylphenyl)triazol-1-yl]methyl]phenyl]pyrimidine	1623887: Inhibition of EphB4 (unknown origin) after 1 hrs by ADP-Glo luminescence assay	ic50	0.0033	uM
1-N-[4-(3-amino-1H-indazol-4-yl)phenyl]-1-N’-[2-bromo-4-(trifluoromethoxy)phenyl]cyclopropane-1,1-dicarboxamide	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0036	uM
N-[5-[4-[(3-chlorophenyl)carbamoylamino]phenyl]-2-pyridinyl]prop-2-enamide	1504163: Inhibition of EphB4 (unknown origin) after 4 hrs by ADP-Glo luminescence assay	ic50	0.0039	uM
N-[3-(7-amino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	383086: Inhibition of EphB4 by cellular assay	ec50	0.0040	uM
[3-[[2-(3,5-dimorpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]-4-methylphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0040	uM
[4-methyl-3-[methyl-[2-[3-(4-methylpiperazin-1-yl)-5-morpholin-4-ylanilino]pyrimidin-4-yl]amino]phenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0040	uM
[3-[[2-(3,5-dimorpholin-4-ylanilino)pyrimidin-4-yl]-ethylamino]-4-methylphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0040	uM
1-N-[4-(3-amino-1H-indazol-4-yl)phenyl]-1-N’-[4-bromo-2-(trifluoromethoxy)phenyl]cyclopropane-1,1-dicarboxamide	1426702: Inhibition of EphB4 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0045	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-[5-bromo-2-(trifluoromethoxy)phenyl]thiourea	1492669: Inhibition of EPHB4 (unknown origin) after 4 hrs by ADP-Glo assay	ic50	0.0047	uM
[3-[[2-(3-methoxy-5-morpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]-4-methylphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0050	uM
[3-[[2-(3,5-dimorpholin-4-ylanilino)pyrimidin-4-yl]-propan-2-ylamino]-4-methylphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0050	uM
3-[4-amino-7-[3-(azetidin-1-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-5-yl]phenol	1290953: Inhibition of EphB4 receptor (unknown origin)	ic50	0.0050	uM
2-amino-1-(5-hydroxy-2-methylphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide	1186108: Inhibition of phosphorylation of full-length myc-tagged human EphB4 overexpressed in mouse embryonic fibroblasts after 90 mins by sandwich ELISA	ic50	0.0054	uM
Bosutinib	507441: Inhibition of EPHB4	ic50	0.0055	uM
4-N-(3-chlorophenyl)-2-N-(3,5-dimorpholin-4-ylphenyl)-4-N-methylpyrimidine-2,4-diamine	591196: Inhibition of human EPHB4	ic50	0.0060	uM
[4-methyl-3-[methyl-[2-[3-morpholin-4-yl-5-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]phenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0060	uM
2-N-(3,5-dimorpholin-4-ylphenyl)-4-N-(6-methoxy-2-pyridinyl)-4-N-methylpyrimidine-2,4-diamine	591196: Inhibition of human EPHB4	ic50	0.0060	uM
[3-[[2-[3-(4-hydroxypiperazin-1-yl)-5-morpholin-4-ylanilino]pyrimidin-4-yl]-methylamino]-4-methylphenyl]methanol	591196: Inhibition of human EPHB4	ic50	0.0070	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
bisphenol A	affects binding, increases methylation	2
perfluorooctanoic acid	decreases expression	2
Arsenic	increases expression, affects methylation, affects cotreatment, increases abundance	2
NVP-BHG712	increases phosphorylation, decreases reaction	1
FR900359	decreases phosphorylation	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
enzacamene	increases expression, affects response to substance, increases reaction	1
beta-methylcholine	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
nutlin 3	increases secretion, affects cotreatment, increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
enzalutamide	increases reaction, affects reaction, decreases cleavage, affects response to substance, affects expression	1
jinfukang	affects cotreatment, increases expression	1
ponatinib	decreases activity	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Dasatinib	affects binding	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	affects cotreatment, decreases expression	1

ChEMBL screening assays

437 unique, capped per target: 437 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4415997	Binding	Protac activity against VHL/EPHB4 in human K562 cells assessed as reduction in EPHB4 protein levels at 1 to 100 nM incubated for 16 hrs by by Western blot analysis	Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. — J Med Chem

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2WK	Abcam HEK293T EPHB4 KO 1	Transformed cell line	Female
CVCL_B2WL	Abcam HEK293T EPHB4 KO 2	Transformed cell line	Female
CVCL_B7X5	Abcam Raji EPHB4 KO	Cancer cell line	Male
CVCL_B9XS	Abcam THP-1 EPHB4 KO	Cancer cell line	Male
CVCL_C6ZM	Abcam PC-3 EPHB4 KO	Cancer cell line	Male
CVCL_SM23	HAP1 EPHB4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04999618	PHASE4	COMPLETED	A New Approach in Laser Surgery Using the Regenerative Solution in Children Diagnosed With Vascular Pathology
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
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
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
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
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
NCT01003951	PHASE2	COMPLETED	Acupuncture for the Treatment of Chronic Lymphedema
NCT01276054	PHASE2	TERMINATED	Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity of Arm Lymphedema in Stage 0-2 Patients.
NCT01318785	PHASE2	UNKNOWN	Therapeutical Assessment of Compression Armsleeves for Lymphatic Indications
NCT01406769	PHASE2	COMPLETED	Bioimpedance Spectroscopy in Detecting Lower-Extremity Lymphedema in Patients With Stage I, Stage II, Stage III, or Stage IV Vulvar Cancer Undergoing Surgery and Lymphadenectomy
NCT02700529	PHASE2	COMPLETED	Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)
NCT02895724	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy to Reduce Lymphedema After Breast Cancer -an Explorative Clinical Trial
NCT03658967	PHASE2	COMPLETED	Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)
NCT03776721	PHASE2	COMPLETED	Treatment of Breast Cancer-related Lymphedema With Stem Cells and Fat Grafting
NCT06494111	PHASE2	RECRUITING	Systemic Therapy of Open-label Prophylactic Pravastatin or Pentoxifylline/Tocopherol Prevention of Lymphedema Advancing to Eventual Fibrosis: an Interventional Registry-embedded Bayesian Randomized Trial for Radiation Sequelae (STOP4-LATE-FIBROSE)
NCT06912763	PHASE2	RECRUITING	Reversing External-beam Radiotherapy-associated Fibrosis Syndrome: an Interventional Bayesian Adaptive Randomized-controlled Orphan Drug Platform Trial for Orodental Sequelae (Reverse-fibrose)
NCT06989099	PHASE2	RECRUITING	Lymphedema Prevention Through Immediate Lymphatic Reconstruction (LILY) Trial.
NCT00318513	PHASE1	UNKNOWN	Safety Study of Bevacizumab to Treat Women With a History of Breast Cancer and Suffering From Upper Extremity Lymphedema
NCT00393497	PHASE1	COMPLETED	A Pilot Study of VEGF Inhibition in Patients With Lymphedema Following Breast Cancer Treatment
NCT01470378	PHASE1	UNKNOWN	Manual Lymphatic Drainage in Women Undergone to Thigh Lifting
NCT02496013	PHASE1	UNKNOWN	Clinical Translation of a Novel Albumin-Binding PET Radiotracer 68Ga-NEB