EPHB3

Summary

EPHB3 (EPH receptor B3, HGNC:3394) is a protein-coding gene on chromosome 3q27.1, encoding Ephrin type-B receptor 3 (P54753). Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.

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 two 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. This gene encodes a receptor for ephrin-B family members.

Source: NCBI Gene 2049 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 127 total
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3394
Approved symbol	EPHB3
Name	EPH receptor B3
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	Hek2, Tyro6
Ensembl gene	ENSG00000182580
Ensembl biotype	protein_coding
OMIM	601839
Entrez	2049

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 retained_intron

ENST00000330394, ENST00000473079, ENST00000482987, ENST00000890161, ENST00000911962, ENST00000957734

RefSeq mRNA: 1 — MANE Select: NM_004443 NM_004443

CCDS: CCDS3268

Canonical transcript exons

ENST00000330394 — 16 exons

Exon	Start	End
ENSE00001290408	184577658	184577817
ENSE00001292514	184578414	184578466
ENSE00001294450	184581253	184581408
ENSE00001298823	184579687	184579934
ENSE00001301799	184571318	184571382
ENSE00001302808	184575830	184575985
ENSE00001309074	184577343	184577467
ENSE00001309998	184580972	184581165
ENSE00001313326	184577898	184578006
ENSE00001316258	184581514	184582408
ENSE00001317406	184561785	184562353
ENSE00001319919	184579477	184579599
ENSE00001324116	184572504	184573176
ENSE00001330737	184576842	184577183
ENSE00002400985	184580729	184580878
ENSE00002480900	184580402	184580617

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 93.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.0282 / max 187.5510, expressed in 1136 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40217	8.3230	1102
40215	0.4971	293
40216	0.2081	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	93.96	silver quality
skin of leg	UBERON:0001511	93.88	gold quality
lower esophagus mucosa	UBERON:0035834	93.35	gold quality
tongue squamous epithelium	UBERON:0006919	93.05	silver quality
skin of abdomen	UBERON:0001416	92.96	gold quality
zone of skin	UBERON:0000014	92.30	gold quality
diaphragm	UBERON:0001103	90.63	gold quality
esophagus mucosa	UBERON:0002469	90.40	gold quality
gingival epithelium	UBERON:0001949	90.27	gold quality
parotid gland	UBERON:0001831	90.14	gold quality
mucosa of transverse colon	UBERON:0004991	89.86	gold quality
gingiva	UBERON:0001828	89.78	gold quality
periodontal ligament	UBERON:0008266	89.75	gold quality
upper arm skin	UBERON:0004263	89.37	gold quality
cervix squamous epithelium	UBERON:0006922	89.35	silver quality
cervix epithelium	UBERON:0004801	88.38	gold quality
hair follicle	UBERON:0002073	88.06	silver quality
squamous epithelium	UBERON:0006914	87.86	gold quality
saliva-secreting gland	UBERON:0001044	87.77	gold quality
type B pancreatic cell	CL:0000169	87.72	silver quality
triceps brachii	UBERON:0001509	87.72	gold quality
rectum	UBERON:0001052	87.66	gold quality
gluteal muscle	UBERON:0002000	87.28	gold quality
mouth mucosa	UBERON:0003729	87.27	gold quality
amniotic fluid	UBERON:0000173	87.10	gold quality
body of stomach	UBERON:0001161	87.09	gold quality
minor salivary gland	UBERON:0001830	87.01	gold quality
cardia of stomach	UBERON:0001162	86.58	gold quality
epithelium of esophagus	UBERON:0001976	86.36	gold quality
ectocervix	UBERON:0012249	86.31	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	16.59
E-ANND-3	yes	6.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL2, CTNNB1, LEF1, TCF7, TXK

miRNA regulators (miRDB)

71 targeting EPHB3, 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-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315

Literature-anchored findings (GeneRIF, showing 24)

• RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. (PMID:11956217)
• while catalytic activity of EphB3 is required for inhibition of integrin-mediated cell adhesion, a distinct signaling pathway to Rho GTPases shared by WT- and KD-EphB3 receptor mediates inhibition of directional cell migration (PMID:15536074)
• EphB3-ephrin-B interaction promotes mesenchymal-to-epithelial transition (MET) by re-establishing epithelial cell-cell junctions and such an MET-promoting effect contributes to EphB3-mediated tumor suppression. (PMID:19483190)
• EPHB3, MASP1 and SST map to 3q26.2-q29 and may have roles in squamous cell carcinoma of the lung (PMID:19607727)
• Ephrin B3 receptor regulates the synthesis and release of D-serine in astrocytes, which may have important implications on synaptic transmission and plasticity. (PMID:21106840)
• EphB3 provides critical support to the development and progression of NSCLC by stimulating cell growth, migration, and survival. (PMID:21266352)
• Data show that EphB receptors interact with E-cadherin and with the metalloproteinase ADAM10 at sites of adhesion. (PMID:21804545)
• Our work shows that EphB3 is consistently expressed by malignant T lymphocytes, most frequently in combination with EphB6, and that stimulation with their common ligands strongly suppresses Fas-induced apoptosis in these cells. (PMID:22039307)
• EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex (PMID:22314363)
• These results uncover enhancer decommissioning as a mechanism for transcriptional silencing of the EPHB3 tumor suppressor. (PMID:24707046)
• results identify EPHB3 as a novel target of SNAIL1 and suggest that disabling EPHB3 signaling is an important aspect to eliminate a roadblock at the onset of EMT processes. (PMID:25277775)
• Study found up-regulated expression of ephrinB3/EphB3 in intractable temporal lobe epilepsy patients and experimental temporal lobe epilepsy rats, which suggested that ephrinB3/EphB3 might be involved in the pathogenesis of temporal lobe epilepsy (PMID:26930615)
• work suggested that EphB3 acted as a tumor promoter in Papillary Thyroid Cancer by increasing the in vitro migration as well as the in vivo metastasis of Papillary Thyroid Cancer cells through regulating the activities of Vav2 and Rho GTPases in a kinase-dependent manner. (PMID:27986811)
• These results show that EphB3 protein is lost in ovarian serous carcinoma and is associated with tumor grade and FIGO stage, which indicate that EphB3 protein may play a role in carcinogenesis of ovarian serous carcinoma and may be used as a molecular marker for prognosis. (PMID:28120491)
• These results indicated the suppressive effect of Form on colon carcinoma cell proliferation and invasion, possibly via miR149induced EphB3 downregulation and the inhibition of the PI3K/AKT and STAT3 signaling pathways. (PMID:29620230)
• FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1. (PMID:29789713)
• Data suggest that receptor-tyrosine kinase HEK2 (EphB3) and phosphatidylinositol 3-kinase catalytic alpha polypeptide (PIK3CA) are cooperating oncogenes that contribute toward its pathogenesis. (PMID:29970482)
• phosphorylation of mTOR through signaling by EphB3 is a potential mechanism of AZD4547 resistance in GC cells (PMID:30044964)
• EZH2-mediated epigenetic suppression of EphB3 inhibits gastric cancer proliferation and metastasis by affecting E-cadherin and vimentin expression. (PMID:30408551)
• Receptor Tyrosine Kinase EphB3: a Prognostic Indicator in Colorectal Carcinoma. (PMID:30535864)
• Expression Profile and Prognostic Significance of EPHB3 in Colorectal Cancer. (PMID:32294981)
• Low Expression of EphB2, EphB3, and EphB4 in Bladder Cancer: Novel Potential Indicators of Muscular Invasion. (PMID:34296545)
• Up-regulated lncRNA SNHG9 mediates the pathogenesis of dilated cardiomyopathy via miR-326/EPHB3 axis. (PMID:37004604)
• EphB3 protein is a potential ancillary diagnostic biomarker for thyroid cancers. (PMID:38150866)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ephb3a	ENSDARG00000031548
danio_rerio	ephb3b	ENSDARG00000103576
danio_rerio		ENSDARG00000109663
mus_musculus	Ephb3	ENSMUSG00000005958
rattus_norvegicus	Ephb3	ENSRNOG00000031801

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 3 — P54753 (reviewed: P54753)

Alternative names: EPH-like tyrosine kinase 2, Embryonic kinase 2, Tyrosine-protein kinase TYRO6

All UniProt accessions (1): P54753

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. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt.

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.

Subcellular location. Cell membrane. Cell projection. Dendrite.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated. Autophosphorylates upon ligand-binding. Autophosphorylation on Tyr-614 is required for interaction with SH2 domain-containing proteins. Ubiquitinated by RNF186, mainly through ‘Lys-48’ and ‘Lys-63’-linked polyubiquitin chains.

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

RefSeq proteins (1): NP_004434* (*=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
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
IPR034245	EphB3_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
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 (67 total): strand 23, helix 13, sequence variant 5, domain 5, sequence conflict 3, turn 3, binding site 2, glycosylation site 2, topological domain 2, mutagenesis site 2, signal peptide 1, chain 1, short sequence motif 1, active site 1, modified residue 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5L6O	X-RAY DIFFRACTION	1.88
3P1I	X-RAY DIFFRACTION	2.1
3ZFY	X-RAY DIFFRACTION	2.2
5L6P	X-RAY DIFFRACTION	2.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54753-F1	82.62	0.51

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): 758 (proton acceptor)

Ligand- & substrate-binding residues (2): 639–647; 665

Post-translational modifications (1): 614

Disulfide bonds (1): 81–199

Glycosylation sites (2): 351, 445

Mutagenesis-validated functional residues (2):

Position	Phenotype
614	partial loss of phosphorylation and loss of interaction with sh2-containing proteins.
665	kinase-dead. loss of autophosphorylation.

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: 236 (showing top): GOBP_DENDRITE_DEVELOPMENT, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, FREAC2_01, GOBP_NEURON_RECOGNITION, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, PEREZ_TP63_TARGETS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_THYMUS_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (24): angiogenesis (GO:0001525), urogenital system development (GO:0001655), axon guidance (GO:0007411), axonal fasciculation (GO:0007413), cell migration (GO:0016477), central nervous system projection neuron axonogenesis (GO:0021952), corpus callosum development (GO:0022038), regulation of cell-cell adhesion (GO:0022407), retinal ganglion cell axon guidance (GO:0031290), substrate adhesion-dependent cell spreading (GO:0034446), ephrin receptor signaling pathway (GO:0048013), thymus development (GO:0048538), digestive tract morphogenesis (GO:0048546), regulation of axonogenesis (GO:0050770), positive regulation of synapse assembly (GO:0051965), roof of mouth development (GO:0060021), dendritic spine development (GO:0060996), dendritic spine morphogenesis (GO:0060997), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), nervous system development (GO:0007399), cell-substrate adhesion (GO:0031589), regulation of GTPase activity (GO:0043087), protein autophosphorylation (GO:0046777)

GO Molecular Function (11): ephrin receptor activity (GO:0005003), transmembrane-ephrin receptor activity (GO:0005005), ATP binding (GO:0005524), axon guidance receptor activity (GO:0008046), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), 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), dendrite (GO:0030425), membrane (GO:0016020), cell projection (GO:0042995)

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	4
anatomical structure development	3
axonogenesis	2
axon guidance	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
system development	1
renal system development	1
neuron projection guidance	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
cell motility	1
central nervous system neuron axonogenesis	1
telencephalon development	1
regulation of cell adhesion	1
cell-cell adhesion	1
cell-substrate adhesion	1
cell surface receptor protein tyrosine kinase signaling pathway	1
hematopoietic or lymphoid organ development	1
gland development	1
tube morphogenesis	1
digestive tract development	1
regulation of neuron projection development	1
regulation of anatomical structure morphogenesis	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
dendrite development	1
neuron projection development	1
neuron projection morphogenesis	1
dendrite morphogenesis	1
dendritic spine development	1
dendritic spine organization	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
transmembrane receptor protein tyrosine kinase activity	1
ephrin receptor signaling pathway	1

Protein interactions and networks

STRING

1774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHB3	EFNB1	P98172	994
EPHB3	EFNB2	P52799	994
EPHB3	EFNB3	Q15768	991
EPHB3	EFNA5	P52803	757
EPHB3	EFNA3	P52797	735
EPHB3	AFDN	P55196	697
EPHB3	EFNA1	P20827	630
EPHB3	SEMA4D	Q92854	625
EPHB3	TCF7L2	Q9NQB0	625
EPHB3	CTNNB1	P35222	614
EPHB3	EFNA2	O43921	610
EPHB3	EFNA4	P52798	602
EPHB3	HNF4A	P41235	561
EPHB3	CDH1	P12830	536
EPHB3	ASCL2	Q99929	527

IntAct

132 interactions, top by confidence:

A	B	Type	Score
HSF2BP	EPHB3	psi-mi:“MI:0915”(physical association)	0.560
HPCAL1	EPHB3	psi-mi:“MI:0915”(physical association)	0.560
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
EPHB3		psi-mi:“MI:0915”(physical association)	0.500
EPHB3	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
NOS1	EPHB3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	EPHB3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	EPHB3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	EPHB3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB3	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (49): EPHB3 (Affinity Capture-MS), EPHB3 (Affinity Capture-MS), EPHB3 (Affinity Capture-MS), EPHB3 (Affinity Capture-MS), EPHB3 (Biochemical Activity), EPHB3 (PCA), EPHB3 (Two-hybrid), EPHB3 (Two-hybrid), EPHB3 (Affinity Capture-MS), EPHB3 (Affinity Capture-Western), EPHB3 (Two-hybrid), EPHB3 (Affinity Capture-Western), EPHB3 (Reconstituted Complex), EFNB3 (Reconstituted Complex), EPHB3 (Reconstituted Complex)

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: A0A8I3NFE2, A5PMU4, D3ZAR1, O09127, O15357, O70143, P0C6S7, P29321, P29353, P54753, P54754, P54755, P54756, P54758, P59672, P98083, Q03145, Q07498, Q09YL6, Q0IIE2, Q2I6J1, Q32PV0, Q3V1H9, Q5M824, Q5PQS4, Q5R7W7, Q5SW96, Q5TGI4, Q60629, Q61120, Q62413, Q6DD51, Q6P549, Q6P9K8, Q6S5L9, Q7Z6G8, Q801G1, Q8BIZ1, Q8C142, Q8K2A1

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
EPHB3	“down-regulates activity”	CDKN1B	phosphorylation
EFNB2	up-regulates	EPHB3	binding
EFNB1	up-regulates	EPHB3	binding
EFNB3	up-regulates	EPHB3	binding
EPHB3	“up-regulates activity”	EPHB3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
Ras activation upon Ca2+ influx through NMDA receptor	5	43.9×	6e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	41.8×	6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	41.8×	6e-06
Assembly and cell surface presentation of NMDA receptors	10	39.0×	1e-11
Dopamine Neurotransmitter Release Cycle	5	38.2×	7e-06
Long-term potentiation	5	36.6×	7e-06
Neurexins and neuroligins	10	30.3×	1e-10
Protein-protein interactions at synapses	6	24.5×	7e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	55.0×	2e-11
receptor clustering	7	46.0×	3e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	8	41.7×	4e-09
protein localization to synapse	5	40.3×	1e-05
cell-cell adhesion	10	10.7×	4e-06
protein-containing complex assembly	6	7.2×	6e-03
chemical synaptic transmission	7	5.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2663 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184575828:A:AG	acceptor_gain	1.0000
3:184575829:G:GG	acceptor_gain	1.0000
3:184575829:GCCT:G	acceptor_gain	1.0000
3:184575981:TACCA:T	donor_gain	1.0000
3:184575984:CA:C	donor_gain	1.0000
3:184575984:CAGTG:C	donor_loss	1.0000
3:184575985:AG:A	donor_loss	1.0000
3:184575986:G:GG	donor_gain	1.0000
3:184575986:G:T	donor_loss	1.0000
3:184575987:T:G	donor_loss	1.0000
3:184575988:GAGT:G	donor_loss	1.0000
3:184576830:T:G	acceptor_gain	1.0000
3:184576832:T:G	acceptor_gain	1.0000
3:184576837:CACAG:C	acceptor_loss	1.0000
3:184576839:C:G	acceptor_gain	1.0000
3:184576839:CAGCC:C	acceptor_loss	1.0000
3:184576840:A:AG	acceptor_gain	1.0000
3:184576840:AGCC:A	acceptor_gain	1.0000
3:184576841:G:GA	acceptor_gain	1.0000
3:184576841:GCC:G	acceptor_gain	1.0000
3:184576841:GCCG:G	acceptor_gain	1.0000
3:184576841:GCCGT:G	acceptor_gain	1.0000
3:184577128:C:T	donor_gain	1.0000
3:184577180:GCTG:G	donor_gain	1.0000
3:184577464:GAAGG:G	donor_loss	1.0000
3:184577466:AG:A	donor_loss	1.0000
3:184577467:GG:G	donor_loss	1.0000
3:184577468:G:T	donor_loss	1.0000
3:184577647:T:TA	acceptor_gain	1.0000
3:184577648:G:A	acceptor_gain	1.0000

AlphaMissense

6505 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184572504:T:A	W62R	1.000
3:184572504:T:C	W62R	1.000
3:184572506:G:C	W62C	1.000
3:184572506:G:T	W62C	1.000
3:184572595:T:C	L92P	1.000
3:184572715:T:C	L132P	1.000
3:184572985:T:G	F222C	1.000
3:184573041:T:A	C241S	1.000
3:184573042:G:A	C241Y	1.000
3:184573042:G:C	C241S	1.000
3:184573043:C:G	C241W	1.000
3:184573086:T:A	C256S	1.000
3:184573087:G:A	C256Y	1.000
3:184573087:G:C	C256S	1.000
3:184573088:C:G	C256W	1.000
3:184573104:T:A	W262R	1.000
3:184573104:T:C	W262R	1.000
3:184573106:G:C	W262C	1.000
3:184573106:G:T	W262C	1.000
3:184575979:T:A	C336S	1.000
3:184575980:G:C	C336S	1.000
3:184575981:T:G	C336W	1.000
3:184576904:T:A	W359R	1.000
3:184576904:T:C	W359R	1.000
3:184576906:G:C	W359C	1.000
3:184576906:G:T	W359C	1.000
3:184577116:C:A	N429K	1.000
3:184577116:C:G	N429K	1.000
3:184577405:T:A	W473R	1.000
3:184577405:T:C	W473R	1.000

dbSNP variants (sampled 300 via entrez): RS1000021850 (3:184573799 C>T), RS1000228497 (3:184567902 T>C), RS1000251018 (3:184579219 G>A), RS1000577143 (3:184567701 G>A), RS1000749616 (3:184566897 T>G), RS1000949698 (3:184561629 C>G,T), RS1001080774 (3:184578050 C>T), RS1001353174 (3:184568138 G>T), RS1001360914 (3:184574300 G>A), RS1001421331 (3:184569666 G>T), RS1001427234 (3:184578199 C>A,T), RS1001600457 (3:184564425 T>C), RS1002024085 (3:184568419 GCTCA>G), RS1002216519 (3:184562967 G>A,C), RS1002247621 (3:184578321 C>A)

Disease associations

OMIM: gene MIM:601839 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003999_2	Nose size	2.000000e-15
GCST007989_7	Facial morphology traits (63 three-dimensional facial segments)	8.000000e-10
GCST010105_118	Nicotine dependence symptom count	5.000000e-06
GCST010105_158	Nicotine dependence symptom count	5.000000e-06
GCST011954_2	White matter hyperintensity volume x hypertension interaction (2df)	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009262	nicotine dependence symptom count
EFO:0005665	white matter hyperintensity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL4901 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 137,588 (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
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL5416410	DASATINIB	4	655
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL206834	BAFETINIB	2	1,024
CHEMBL3039525	GOLVATINIB	2	535
CHEMBL3545396	BMS-690514	2	567
CHEMBL3991932	PEXMETINIB	2	409
CHEMBL402548	DANUSERTIB	2	1,928
CHEMBL564829	MILCICLIB	2	821
CHEMBL259084	MLN-8054	1	2,430
CHEMBL3544932	TAK-901	1	557
CHEMBL3545360	ASP-3026	1	665

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 66 [PMID: 19788238]	Inhibition	7.82	pIC50
compound 20 [PMID: 23489211]	Inhibition	5.36	pIC50

Binding affinities (BindingDB)

3 measured of 4 human assays (4 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
BMS-354825	KD	27 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
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM

ChEMBL bioactivities

70 potent at pChembl≥5 of 88 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	Kd	2	nM	CHEMBL400402
8.22	IC50	6	nM	CHEMBL3752910
8.16	Kd	6.9	nM	DASATINIB
8.15	IC50	7	nM	CHEMBL3321809
8.15	IC50	7	nM	CHEMBL5191665
8.15	IC50	7	nM	CHEMBL5203261
7.82	IC50	15	nM	CHEMBL566515
7.76	IC50	17.4	nM	DASATINIB ANHYDROUS
7.75	IC50	18	nM	CHEMBL5202826
7.71	IC50	19.5	nM	CHEMBL4638981
7.54	Kd	29	nM	DASATINIB
7.54	Kd	29	nM	DASATINIB ANHYDROUS
7.54	Kd	28.84	nM	DASATINIB ANHYDROUS
7.30	IC50	50.5	nM	CHEMBL4640297
7.22	IC50	60	nM	CHEMBL1078739
7.20	IC50	63	nM	CHEMBL1078214
7.18	IC50	66	nM	CHEMBL1078107
7.11	IC50	77	nM	CHEMBL1077571
7.10	IC50	79	nM	CHEMBL1077739
7.09	Kd	81	nM	CHEMBL249097
7.07	Kd	85	nM	FORETINIB
7.06	IC50	87	nM	CHEMBL1078840
6.76	Kd	175	nM	DANUSERTIB
6.76	IC50	173	nM	CHEMBL1077741
6.72	IC50	191	nM	CHEMBL5653589
6.72	IC50	190	nM	CHEMBL1080959
6.70	IC50	200	nM	CHEMBL1078108
6.68	Kd	210	nM	BOSUTINIB
6.64	IC50	228	nM	CHEMBL1077740
6.62	IC50	240	nM	CHEMBL1078109
6.58	IC50	260	nM	CHEMBL1081498
6.47	Kd	340	nM	CHEMBL386051
6.46	IC50	350	nM	CHEMBL1916891
6.34	IC50	460	nM	CHEMBL1078738
6.26	Kd	547	nM	PONATINIB
6.13	IC50	741	nM	STAUROSPORINE
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	IC50	1000	nM	CHEMBL1078785
6.00	Kd	1000	nM	NILOTINIB
5.96	IC50	1090	nM	CHEMBL1952210
5.90	IC50	1250	nM	CHEMBL606964
5.88	IC50	1320	nM	STAUROSPORINE
5.85	Kd	1400	nM	LINIFANIB
5.82	Kd	1529	nM	BOSUTINIB
5.74	IC50	1830	nM	STAUROSPORINE
5.72	Kd	1900	nM	TAE-684
5.70	IC50	2000	nM	CHEMBL1080957
5.64	Kd	2314	nM	CHEMBL3752910

PubChem BioAssay actives

64 with measured affinity, of 1092 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
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1424993: 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	0.0020	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147748: Inhibition of Nano Luc-fused full length C-terminal EPHB3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0060	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	435159: Binding constant for EPHB3 kinase domain	kd	0.0069	uM
2-amino-1-(2-chloro-3-hydroxy-6-methylphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide	1885734: Inhibition of full length Nano-luc fused EPHB3 in human HEK-293T cells incubated for 2 hrs by cell based NanoBRET target engagement assay	ic50	0.0070	uM
2-amino-1-(5-hydroxy-2-methylphenyl)pyrrolo[2,3-b]quinoline-3-carboxamide	1885734: Inhibition of full length Nano-luc fused EPHB3 in human HEK-293T cells incubated for 2 hrs by cell based NanoBRET target engagement assay	ic50	0.0070	uM
2-amino-1-(5-hydroxy-2-methylphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide	1885734: Inhibition of full length Nano-luc fused EPHB3 in human HEK-293T cells incubated for 2 hrs by cell based NanoBRET target engagement assay	ic50	0.0070	uM
7-(5-hydroxy-2-methylphenyl)-6-(2-methoxyphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione	441394: Inhibition of EphB3 by [gamma33-P]ATP based assay	ic50	0.0150	uM
Dasatinib	2147748: Inhibition of Nano Luc-fused full length C-terminal EPHB3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0174	uM
2-amino-1-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide	1885734: Inhibition of full length Nano-luc fused EPHB3 in human HEK-293T cells incubated for 2 hrs by cell based NanoBRET target engagement assay	ic50	0.0180	uM
N-[3-chloro-4-(4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-5-ylmethyl)phenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648816: Inhibition of EPHB3 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0195	uM
N-[4-(1,3a,4,5,7,7a-hexahydropyrazolo[3,4-c]pyridin-6-ylmethyl)-3-chlorophenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648816: Inhibition of EPHB3 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0505	uM
N-(2-chlorophenyl)-6-phenylimidazo[1,2-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0600	uM
N-(2-chlorophenyl)-5-piperidin-1-ylpyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0630	uM
N-(2-chlorophenyl)-5-phenylpyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0660	uM
N-(2-chlorophenyl)-5-(dimethylamino)pyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0770	uM
N-(2-chlorophenyl)-6-piperidin-4-ylimidazo[1,2-a]pyridine-3-carboxamide;oxalic acid	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0790	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389076: Binding affinity to human EPHB3	kd	0.0810	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624955: Binding constant for EPHB3 kinase domain	kd	0.0850	uM
N-(2-chlorophenyl)-6-piperidin-1-ylimidazo[1,2-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.0870	uM
6-bromo-N-(2-chlorophenyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.1730	uM
N-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide	1424993: 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	0.1750	uM
N-(2-chlorophenyl)-5-methoxypyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.1900	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147748: Inhibition of Nano Luc-fused full length C-terminal EPHB3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.1910	uM
N-(2-chlorophenyl)-5-pyrrol-1-ylpyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.2000	uM
Bosutinib	624955: Binding constant for EPHB3 kinase domain	kd	0.2100	uM
N-(2-chlorophenyl)-6-(4-hydroxypiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.2280	uM
N-(2-chlorophenyl)-5-morpholin-4-ylpyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.2400	uM
N-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.2600	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624955: Binding constant for EPHB3 kinase domain	kd	0.3400	uM
(E)-4-(dimethylamino)-N-[7-fluoro-4-(2-methylanilino)imidazo[1,5-a]quinoxalin-8-yl]-N-methylbut-2-enamide	629835: Inhibition of EPHB3 relative to control	ic50	0.3500	uM
N-(2-chlorophenyl)imidazo[1,2-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	0.4600	uM
Ponatinib	1424993: 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	0.5470	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715359: Inhibition of human EPHB3 using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.7410	uM
N-(2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	1.0000	uM
Nilotinib	624955: Binding constant for EPHB3 kinase domain	kd	1.0000	uM
7-anilino-1-[(1R,3R)-3-hydroxycyclopentyl]-3-(4-methoxyphenyl)-4H-pyrimido[4,5-d]pyrimidin-2-one	645935: Inhibition of EphB3	ic50	1.0900	uM
7-(4-fluoroanilino)-1-[(1R,3R)-3-hydroxycyclopentyl]-3-(4-methoxyphenyl)-4H-pyrimido[4,5-d]pyrimidin-2-one	263417: Inhibitory activity against EphB3	ic50	1.2500	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	435159: Binding constant for EPHB3 kinase domain	kd	1.4000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624955: Binding constant for EPHB3 kinase domain	kd	1.9000	uM
5-chloro-N-(2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide	469644: Inhibition of human recombinant EphB3 kinase-mediated BTK-peptide phosphorylation assessed as 33P incorporation after 30 mins by scintillation counting	ic50	2.0000	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1424993: 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	2.3490	uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide	1424993: 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	2.5980	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1424993: 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	2.6520	uM
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	435159: Binding constant for EPHB3 kinase domain	kd	3.5000	uM
(2S)-2-[[(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1260969: Displacement of biotinylated ephrin-B1-Fc from EphB3 (unknown origin) preincubated for 1 hr followed by biotinylated-ephrin-B1-Fc addition measured after 4 hrs by ELISA	ic50	3.9000	uM
(2S)-2-[[(4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	728710: Displacement of ephrin-B1-Fc from EphB3 receptor Fc ectodomain (unknown origin) after 1 hr by ELISA	ic50	4.4000	uM
4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide	1424993: 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	4.5460	uM
1-N’-[2-fluoro-4-[[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]-4-pyridinyl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1424993: 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	4.8240	uM
Tivozanib	1424993: 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	5.4330	uM
2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine	1424993: 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	5.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, decreases methylation	3
Valproic Acid	affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cadmium Chloride	increases expression, decreases expression	2
propionaldehyde	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
15-acetyldeoxynivalenol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
ponatinib	decreases activity	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benztropine	affects cotreatment, decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Clozapine	increases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1

ChEMBL screening assays

281 unique, capped per target: 281 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024914	Binding	Binding affinity to human EPHB3 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RE	Abcam HeLa EPHB3 KO	Cancer cell line	Female
CVCL_SM22	HAP1 EPHB3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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