EPHB6

Summary

EPHB6 (EPH receptor B6, HGNC:3396) is a protein-coding gene on chromosome 7q34, encoding Ephrin type-B receptor 6 (O15197). Kinase-defective receptor for members of the ephrin-B family.

This gene encodes a member of a family of transmembrane proteins that function as receptors for ephrin-B family proteins. Unlike other members of this family, the encoded protein does not contain a functional kinase domain. Activity of this protein can influence cell adhesion and migration. Expression of this gene is downregulated during tumor progression, suggesting that the protein may suppress tumor invasion and metastasis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2051 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 175 total
• Druggable target: yes — 50 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004445

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3396
Approved symbol	EPHB6
Name	EPH receptor B6
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	HEP
Ensembl gene	ENSG00000106123
Ensembl biotype	protein_coding
OMIM	602757
Entrez	2051

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000422643, ENST00000471581, ENST00000476059, ENST00000486511, ENST00000497095, ENST00000611578, ENST00000614832, ENST00000616380, ENST00000617632, ENST00000619012, ENST00000652003, ENST00000886646, ENST00000886648, ENST00000886649, ENST00000886650, ENST00000886651, ENST00000886652, ENST00000886653, ENST00000937289, ENST00000937290, ENST00000937291, ENST00000937292, ENST00000937293, ENST00000940976, ENST00000940977, ENST00000940978

RefSeq mRNA: 3 — MANE Select: NM_004445 NM_001280794, NM_001280795, NM_004445

CCDS: CCDS5873

Canonical transcript exons

ENST00000632037 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4627 / max 459.6374, expressed in 1086 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81736	6.5492	1027
81735	0.6121	142
81730	0.4392	128
81732	0.4328	142
81737	0.1048	50
81733	0.0905	39
81729	0.0863	49
81731	0.0748	34
81734	0.0730	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primary visual cortex	UBERON:0002436	98.99	gold quality
superior frontal gyrus	UBERON:0002661	98.53	gold quality
putamen	UBERON:0001874	98.28	gold quality
caudate nucleus	UBERON:0001873	97.84	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.73	gold quality
right frontal lobe	UBERON:0002810	97.67	gold quality
anterior cingulate cortex	UBERON:0009835	97.41	gold quality
skin of abdomen	UBERON:0001416	97.36	gold quality
frontal cortex	UBERON:0001870	97.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.12	gold quality
zone of skin	UBERON:0000014	97.11	gold quality
prefrontal cortex	UBERON:0000451	97.05	gold quality
skin of leg	UBERON:0001511	96.94	gold quality
nucleus accumbens	UBERON:0001882	96.60	gold quality
ganglionic eminence	UBERON:0004023	96.40	gold quality
cerebral cortex	UBERON:0000956	96.12	gold quality
temporal lobe	UBERON:0001871	92.86	gold quality
amygdala	UBERON:0001876	92.78	gold quality
vagina	UBERON:0000996	92.76	gold quality
lower esophagus mucosa	UBERON:0035834	92.70	gold quality
endocervix	UBERON:0000458	92.44	gold quality
ectocervix	UBERON:0012249	91.78	gold quality
brain	UBERON:0000955	91.39	gold quality
prostate gland	UBERON:0002367	91.31	gold quality
left uterine tube	UBERON:0001303	90.80	gold quality
uterine cervix	UBERON:0000002	90.66	gold quality
right uterine tube	UBERON:0001302	90.04	gold quality
Ammon’s horn	UBERON:0001954	89.72	gold quality
body of pancreas	UBERON:0001150	89.36	gold quality
cortical plate	UBERON:0005343	88.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting EPHB6, 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-3151-5P	99.86	63.83	1069
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-3917	88.03	62.50	44

Literature-anchored findings (GeneRIF, showing 40)

• Cross-linking of EphB6 alters profiles of lymphokine secretion, inhibits proliferation, induces Fas-mediated apoptosis of Jurkat leukemic T cells, and transduces signals into the cells via proteins it associates with. (PMID:11466354)
• interaction between EphB6 and its ligands facilitates T cell responses to antigen (PMID:12393850)
• EphB6 may play an important role in regulating thymocyte differentiation and modulating responses of mature T cells. (PMID:12517763)
• lower EphB6 expression has a role in melanoma progression to metastatic disease (PMID:14612926)
• EphB6 can both positively and negatively regulate cell adhesion and migration (PMID:15955811)
• The potential significance of EphB6 to serve as a diagnostic and prognostic indicator is discussed. (PMID:16364251)
• the two peptides derived from EphB6v might be appropriate targets for peptide-based specific immunotherapy for HLA-A2(+) patients with various cancers (PMID:18754880)
• CLL B-cells showed a more heterogeneous Eph/EFN profile, specially EFNA4, EphB6 and EphA10. EphB6 and EFNA4 were further related with the clinical course of CLL. (PMID:18819711)
• EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. (PMID:19234485)
• The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma. (PMID:19513565)
• Findings suggest a new role for EphB6 in suppressing cancer invasiveness and cell attachment through c-Cbl-dependent signaling. (PMID:20086179)
• The loss of EPHB6 expression in more aggressive breast carcinoma cell lines is regulated in a methylation-dependent manner. The EPHB6 methylation-specific PCR has clinical implications for the prognosis and/or diagnosis of breast and other cancer types (PMID:20181626)
• expression of more than 70 proteins was altered in EphB6-transfected MDA-MB-231 cells; proteins are involved in glycolysis, cell cycle regulation, tumor suppression, cell proliferation, mitochondrial metabolism, mRNA splicing, DNA replication and repair (PMID:20952760)
• Nonsynonymous variants of EPHB6 is associated with familial colorectal cancer. (PMID:21351276)
• results indicate that tumor invasiveness-suppressing activity of EPHB6 is mediated by its ability to sequester other kinase-sufficient and oncogenic EPH receptors (PMID:21737611)
• The alterations in miRNAs and their target mRNAs also suggest indirect involvement of EphB6 in PI3K/Akt/mTOR pathways. (PMID:21811619)
• Data found significant correlations between ephA2, ephA4, ephA7, ephB4, and ephB6 and overall and/or recurrence-free survival in large microarray datasets. (PMID:21935409)
• 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)
• We demonstrate that EphB6 reexpression forces metastatic melanoma cells to deviate from the canonical migration pattern observed in the chick embryo transplant model (PMID:24836890)
• Results suggest that erythropoietin-producing hepatocyte (Eph) receptor B6 (EphB6) may represent a useful tissue biomarker for the prediction of survival rate in colorectal cancers (CRCs). (PMID:24912672)
• EphB6 also interacts with the Hsp90 chaperone. (PMID:25152371)
• These findings implicate EphB6 as a negative regulator of EphA2 oncogenic signaling. (PMID:25239188)
• Studies clearly demonstrate an inverse relationship between the levels of phospho-ERK and the abundance of cadherin 17, beta-catenin and phospho-GSK3beta in EPHB6-expressing MDA-MB-231 cells. (PMID:25331796)
• Enhanced EphB6 expression was significantly associated with Thyroid Lesions. (PMID:26220827)
• EphB6 is a new biomarker for distinguishing high- and low-grade ovarian serous carcinoma, and may be a potential prognostic marker in ovarian serous carcinomas. (PMID:26468391)
• EphB6 protein may be used as a new marker for prognosis for tongue squamous cell carcinoma. (PMID:26617870)
• Study is the first to demonstrate that EphB6 overexpression together with Apc gene mutations may enhance proliferation, invasion and metastasis by colorectal epithelial cells. (PMID:27145271)
• Melanomas from geographically different regions in New Zealand have markedly different mutation frequencies, in particular in the NRAS and EPHB6 genes, when compared to The Cancer Genome Atlas database or other populations. These data have implications for the causation and treatment of malignant melanoma in New Zealand. (PMID:27191502)
• SRC kinase is a synthetic lethality partner of EPHB6 in triple-negative breast cancer cells (PMID:27418135)
• Authors provide evidence that an intrinsically kinase-inactive member of the Eph group of receptor tyrosine kinases, EPHB6, induces marked fragmentation of the mitochondrial network in breast cancer cells of triple-negative origin, lacking expression of the estrogen, progesterone and HER2 receptors. (PMID:27788485)
• using an EphB6 mouse knockout model we found that the loss of EphB6 does not initiate intestinal tumorigenesis and is not involved in the early tumor progression through the adenoma-to-carcinoma transition. (PMID:28262839)
• Data indicate that EphB6 protein was decreased in gastric carcinoma compared with normal mucosa. Analytic results based on pathological parameters suggests that EphB6 protein may inhibit metastasis of gastric carcinoma. (PMID:28453458)
• Low EPHB6 expression is associated with prostate cancer metastasis. (PMID:28826721)
• observations highlight a novel role for EphB6 in reducing drug resistance of T-ALL and suggest that doxorubicin treatment should produce better results if personalised based on EphB6 levels (PMID:29116180)
• It may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment. (PMID:29700392)
• Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism. (PMID:30262919)
• This study demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. (PMID:31160603)
• LncRNA DGCR5 regulates the non-small cell lung cancer cell growth, migration, and invasion through regulating miR-211-5p/EPHB6 axis. (PMID:31241800)
• Cataloguing the dead: breathing new life into pseudokinase research. (PMID:32053275)
• DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. (PMID:32754286)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ephb6	ENSMUSG00000029869
rattus_norvegicus	Ephb6	ENSRNOG00000014367

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), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Ephrin type-B receptor 6 — O15197 (reviewed: O15197)

Alternative names: HEP, Tyrosine-protein kinase-defective receptor EPH-6

All UniProt accessions (4): A0A087WTE3, A0A087WYP8, A0A087WZL4, F8WCM8

UniProt curated annotations — full annotation on UniProt →

Function. Kinase-defective receptor for members of the ephrin-B family. Binds to ephrin-B1 and ephrin-B2. Modulates cell adhesion and migration by exerting both positive and negative effects upon stimulation with ephrin-B2. Inhibits JNK activation, T-cell receptor-induced IL-2 secretion and CD25 expression upon stimulation with ephrin-B2.

Subunit / interactions. Interacts with CBL and EPHB1. Interacts with FYN; this interaction takes place in a ligand-independent manner.

Subcellular location. Membrane Secreted.

Tissue specificity. Expressed in brain. Expressed in non invasive breast carcinoma cell lines (at protein level). Strong expression in brain and pancreas, and weak expression in other tissues, such as heart, placenta, lung, liver, skeletal muscle and kidney. Expressed in breast non invasive tumors but not in metastatic lesions. Isoform 3 is expressed in cell lines of glioblastomas, anaplastic astrocytomas, gliosarcomas and astrocytomas. Isoform 3 is not detected in normal tissues.

Post-translational modifications. Ligand-binding increases phosphorylation on tyrosine residues. Phosphorylation on tyrosine residues is mediated by transphosphorylation by the catalytically active EPHB1 in a ligand-independent manner. Tyrosine phosphorylation of the receptor may act as a switch on the functional transition from cell adhesion/attraction to de-adhesion/repulsion.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive. Its extracellular domain is capable of promoting cell adhesion and migration in response to low concentrations of ephrin-B2, but its cytoplasmic domain is essential for cell repulsion and inhibition of migration induced by high concentrations of ephrin-B2.

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

Isoforms (3)

UniProt ID	Names	Canonical?
O15197-1	1	yes
O15197-2	2
O15197-3	3, EphB6v

RefSeq proteins (3): NP_001267723, NP_001267724, NP_004436* (*=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
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
IPR027936	EPH_TM	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF01404, PF07647, PF07699, PF07714, PF14575, PF25599

UniProt features (74 total): strand 32, sequence variant 18, domain 5, turn 4, splice variant 3, topological domain 2, helix 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, binding site 1, glycosylation site 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7K7J	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15197-F1	81.36	0.46

Functional residue map

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

Ligand- & substrate-binding residues (1): 676–684

Glycosylation sites (1): 480

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: 204 (showing top): RNGTGGGC_UNKNOWN, MODULE_255, JAEGER_METASTASIS_DN, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, MODULE_64, MODULE_317, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_NEUROGENESIS, GGGTGGRR_PAX4_03, CHANDRAN_METASTASIS_DN, CEBPB_01, NFKB_C, SOX9_B1, MYOD_01, GOBP_EPHRIN_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (8): axon guidance (GO:0007411), ephrin receptor signaling pathway (GO:0048013), type IV hypersensitivity (GO:0001806), T cell mediated immunity (GO:0002456), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), activated T cell proliferation (GO:0050798), positive regulation of T cell costimulation (GO:2000525)

GO Molecular Function (8): ephrin receptor activity (GO:0005003), transmembrane-ephrin receptor activity (GO:0005005), ATP binding (GO:0005524), signaling receptor activity (GO:0038023), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transmembrane receptor protein tyrosine kinase activity (GO:0004714), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), dendrite (GO:0030425), cell surface (GO:0009986), 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	4
axonogenesis	1
neuron projection guidance	1
cell surface receptor protein tyrosine kinase signaling pathway	1
T cell mediated immunity	1
hypersensitivity	1
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
T cell proliferation	1
T cell costimulation	1
positive regulation of T cell activation	1
regulation of T cell costimulation	1
transmembrane receptor protein tyrosine kinase activity	1
ephrin receptor signaling pathway	1
ephrin receptor activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
molecular transducer activity	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 tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1

Protein interactions and networks

STRING

1502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHB6	EFNB3	Q15768	998
EPHB6	EFNB1	P98172	994
EPHB6	EFNB2	P52799	992
EPHB6	EFNA1	P20827	831
EPHB6	EFNA5	P52803	813
EPHB6	EFNA3	P52797	798
EPHB6	EFNA4	P52798	796
EPHB6	EFNA2	O43921	777
EPHB6	EPHB1	P54762	777
EPHB6	EPHB4	P54760	581
EPHB6	EPHB2	P29323	461
EPHB6	SEMA3C	Q99985	454
EPHB6	EPHA2	P29317	452
EPHB6	PTK7	Q13308	452
EPHB6	PRSS58	Q8IYP2	448

IntAct

138 interactions, top by confidence:

A	B	Type	Score
HSP90AB1	EPHB6	psi-mi:“MI:0915”(physical association)	0.600
EPHB6	FKBP5	psi-mi:“MI:0914”(association)	0.570
EPHB6	GOPC	psi-mi:“MI:0407”(direct interaction)	0.570
EPHB6	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.570
EPHB6	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	IL16	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHB6	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (89): REL (Two-hybrid), TCF4 (Two-hybrid), TRIM39 (Two-hybrid), NIF3L1 (Two-hybrid), INCA1 (Two-hybrid), NOTCH2NL (Two-hybrid), DUSP18 (Two-hybrid), DUSP19 (Two-hybrid), STYX (Two-hybrid), EPHB6 (PCA), EPHB6 (Two-hybrid), EPHB6 (Two-hybrid), POU6F2 (Two-hybrid), MSX2 (Two-hybrid), DDIT4L (Two-hybrid)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A0A6I8TCE0, A2A8L5, A2AJX4, A7MBJ4, B0X4T2, B3EWZ5, B3EWZ6, B3EX02, B7T7N1, F1NWE3, O00533, O15197, P0C0K6, P10586, P13944, P14781, P23468, P29317, P35331, P35832, P60755, P60756, P70232, P85171, P97686, P98073, Q07497, Q0PMG2, Q0WYX8, Q13332, Q1KL86, Q28902, Q3UH53, Q58EX2, Q5VYJ5, Q60ZN5, Q61330, Q64487, Q64604, Q6V4S5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EPHB6	“up-regulates activity”	CBLC	binding
EPHB6	“down-regulates activity”	EPHA2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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	48.4×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	46.1×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	46.1×	3e-06
Assembly and cell surface presentation of NMDA receptors	10	43.0×	2e-12
Dopamine Neurotransmitter Release Cycle	5	42.1×	4e-06
Long-term potentiation	5	40.3×	4e-06
Neurexins and neuroligins	11	36.7×	1e-12
Protein-protein interactions at synapses	7	31.5×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	66.0×	1e-13
protein localization to synapse	6	52.2×	2e-07
receptor clustering	7	49.6×	2e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	6	33.8×	2e-06
bicellular tight junction assembly	5	18.8×	3e-04
protein-containing complex assembly	9	11.7×	6e-06
cell-cell adhesion	10	11.5×	2e-06
chemical synaptic transmission	8	7.0×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	139
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2640 predictions. Top by Δscore:

Variant	Effect	Δscore
7:142855385:GGT:G	donor_loss	1.0000
7:142855386:GT:G	donor_loss	1.0000
7:142855387:T:G	donor_loss	1.0000
7:142861148:G:GT	donor_gain	1.0000
7:142861184:G:GT	donor_gain	1.0000
7:142866474:A:AG	acceptor_gain	1.0000
7:142866475:C:G	acceptor_gain	1.0000
7:142866479:A:AG	acceptor_gain	1.0000
7:142866479:AGT:A	acceptor_gain	1.0000
7:142866480:G:GA	acceptor_gain	1.0000
7:142866480:GT:G	acceptor_gain	1.0000
7:142866480:GTG:G	acceptor_gain	1.0000
7:142866480:GTGC:G	acceptor_gain	1.0000
7:142866480:GTGCC:G	acceptor_gain	1.0000
7:142866606:G:GG	donor_gain	1.0000
7:142867720:GCG:G	donor_gain	1.0000
7:142867723:G:GG	donor_gain	1.0000
7:142867724:T:G	donor_loss	1.0000
7:142868236:TCCA:T	acceptor_loss	1.0000
7:142868239:A:AG	acceptor_gain	1.0000
7:142868239:AG:A	acceptor_gain	1.0000
7:142868240:G:GA	acceptor_gain	1.0000
7:142868240:GG:G	acceptor_gain	1.0000
7:142868240:GGA:G	acceptor_gain	1.0000
7:142868240:GGAC:G	acceptor_gain	1.0000
7:142868315:G:GT	donor_gain	1.0000
7:142868315:G:T	donor_gain	1.0000
7:142868345:G:GT	donor_gain	1.0000
7:142868357:ACAG:A	donor_loss	1.0000
7:142868359:AG:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000023271 (7:142865779 C>A,G,T), RS1000202562 (7:142854967 G>A,C), RS1000237110 (7:142855591 C>T), RS1000245258 (7:142859386 G>A), RS1000642681 (7:142871323 C>T), RS1001230726 (7:142856608 A>G), RS1001261703 (7:142856281 G>A), RS1001353204 (7:142860083 A>G), RS1001572732 (7:142854305 A>G), RS1002083667 (7:142870427 A>G,T), RS1002376817 (7:142863008 G>A,C), RS1002584530 (7:142867536 G>A), RS1002907570 (7:142857804 A>G), RS1002938672 (7:142857570 T>C), RS1002940838 (7:142867289 C>T)

Disease associations

OMIM: gene MIM:602757 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): newborn respiratory distress syndrome (MONDO:0700081), myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004860_114	Alcoholic chronic pancreatitis	2.000000e-07
GCST004860_42	Alcoholic chronic pancreatitis	2.000000e-06
GCST004860_80	Alcoholic chronic pancreatitis	3.000000e-06
GCST005275_22	Cancer	3.000000e-07
GCST006585_343	Blood protein levels	9.000000e-15
GCST006585_742	Blood protein levels	6.000000e-20

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL5836 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

50 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 536,110 (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
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4
CHEMBL939	GEFITINIB	4
CHEMBL217092	SARACATINIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL377300	BRIVANIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 20 [PMID: 23489211]	Inhibition	5.24	pIC50

ChEMBL bioactivities

91 potent at pChembl≥5 of 96 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.41	Kd	0.039	nM	DASATINIB
9.22	Kd	0.6	nM	CHEMBL400402
8.89	Kd	1.3	nM	FORETINIB
8.70	Kd	2	nM	CHEMBL386051
8.30	Kd	5	nM	CHEMBL1908396
8.22	Kd	6	nM	CRIZOTINIB
8.15	Kd	7	nM	FGFR INHIBITOR DEBIO 1347
8.00	Kd	10	nM	CHEMBL5415503
7.92	Kd	12	nM	AT-9283
7.58	Kd	26	nM	XL-228
7.55	Kd	28	nM	TOZASERTIB
7.48	Kd	33	nM	LINIFANIB
7.47	Kd	34	nM	DASATINIB
7.47	Kd	34	nM	DASATINIB ANHYDROUS
7.46	Kd	34.36	nM	DASATINIB ANHYDROUS
7.37	Kd	43	nM	RAF-265
7.30	Kd	50	nM	DEFOSBARASERTIB
7.14	Kd	73	nM	CYC-116
7.12	Kd	76	nM	VANDETANIB
7.09	Kd	81	nM	PAZOPANIB
7.01	Kd	98	nM	LESTAURTINIB
6.89	Kd	130	nM	CHEMBL311959
6.89	Kd	130	nM	KW-2449
6.85	Kd	140	nM	NINTEDANIB
6.83	IC50	147.2	nM	DASATINIB ANHYDROUS
6.78	Kd	167	nM	DANUSERTIB
6.68	Kd	210	nM	STAUROSPORINE
6.66	Kd	220	nM	CEDIRANIB
6.66	Kd	220	nM	DOVITINIB
6.65	Kd	226	nM	OSI-632
6.65	Kd	224	nM	CHEMBL3752910
6.65	Kd	223.9	nM	CHEMBL3752910
6.62	Kd	241	nM	GILTERITINIB
6.62	Kd	240	nM	SORAFENIB
6.59	Kd	259	nM	TESEVATINIB
6.59	Kd	255	nM	GOLVATINIB
6.52	Kd	300	nM	FEDRATINIB
6.51	Kd	310	nM	R-406
6.47	Kd	337	nM	ADAVOSERTIB
6.46	Kd	350	nM	TAE-684
6.44	ED50	364.3	nM	CHEMBL3752910
6.44	Kd	360	nM	AXITINIB
6.38	Kd	412	nM	DABRAFENIB
6.35	Kd	451	nM	TAK-901
6.30	Kd	500	nM	NILOTINIB
6.28	Kd	521	nM	CHEMBL3688339
6.26	Kd	545	nM	CRIZOTINIB
6.24	Kd	570	nM	FORETINIB
6.24	Kd	570	nM	CHEMBL4465866
6.19	Kd	640	nM	CANERTINIB

PubChem BioAssay actives

85 with measured affinity, of 388 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
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624957: Binding constant for EPHB6 kinase domain	kd	<0.0001	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1424995: 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	0.0006	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	624957: Binding constant for EPHB6 kinase domain	kd	0.0013	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624957: Binding constant for EPHB6 kinase domain	kd	0.0020	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-methoxyphenyl]-3-[1-(1,3-thiazol-2-yl)ethyl]urea	624957: Binding constant for EPHB6 kinase domain	kd	0.0050	uM
Crizotinib	624957: Binding constant for EPHB6 kinase domain	kd	0.0060	uM
[5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone	1424995: 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	0.0070	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988536: Binding affinity to EPHB6 (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0100	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1424995: 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	0.0120	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine	1424995: 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	0.0260	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624957: Binding constant for EPHB6 kinase domain	kd	0.0280	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	624957: Binding constant for EPHB6 kinase domain	kd	0.0330	uM
Dasatinib	2147762: Binding affinity to human EPHB6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0340	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	624957: Binding constant for EPHB6 kinase domain	kd	0.0430	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	624957: Binding constant for EPHB6 kinase domain	kd	0.0500	uM
4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1424995: 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	0.0730	uM
Vandetanib	624957: Binding constant for EPHB6 kinase domain	kd	0.0760	uM
Pazopanib	624957: Binding constant for EPHB6 kinase domain	kd	0.0810	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507931: Binding affinity to EPHB6	kd	0.0980	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624957: Binding constant for EPHB6 kinase domain	kd	0.1300	uM
6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673296: Binding affinity to human wild type partial length EphB6 (Q634 to P948 residues) expressed in mammalian expression system by Kinomescan method	kd	0.1300	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624957: Binding constant for EPHB6 kinase domain	kd	0.1400	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	1424995: 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	0.1670	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	624957: Binding constant for EPHB6 kinase domain	kd	0.2100	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	624957: Binding constant for EPHB6 kinase domain	kd	0.2200	uM
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	624957: Binding constant for EPHB6 kinase domain	kd	0.2200	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147762: Binding affinity to human EPHB6 incubated for 45 mins by Kinobead based pull down assay	kd	0.2239	uM
3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide	1424995: 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	0.2260	uM
Sorafenib	507931: Binding affinity to EPHB6	kd	0.2400	uM
Gilteritinib	1424995: 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	0.2410	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	1424995: 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	0.2550	uM
7-[[(3aS,6aR)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methoxy]-N-(3,4-dichloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine	1424995: 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	0.2590	uM
Fedratinib	624957: Binding constant for EPHB6 kinase domain	kd	0.3000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624957: Binding constant for EPHB6 kinase domain	kd	0.3100	uM
1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one	1424995: 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	0.3370	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	624957: Binding constant for EPHB6 kinase domain	kd	0.3500	uM
Axitinib	624957: Binding constant for EPHB6 kinase domain	kd	0.3600	uM
Dabrafenib	1424995: 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	0.4120	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1424995: 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	0.4510	uM
Nilotinib	624957: Binding constant for EPHB6 kinase domain	kd	0.5000	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1424995: 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	0.5210	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526144: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged EPHB6 (unknown origin) (683 to 1130 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.5700	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624957: Binding constant for EPHB6 kinase domain	kd	0.6400	uM
6-bromo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673296: Binding affinity to human wild type partial length EphB6 (Q634 to P948 residues) expressed in mammalian expression system by Kinomescan method	kd	0.7100	uM
Sunitinib	507931: Binding affinity to EPHB6	kd	0.8500	uM
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	624957: Binding constant for EPHB6 kinase domain	kd	0.8600	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624957: Binding constant for EPHB6 kinase domain	kd	1.1000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624957: Binding constant for EPHB6 kinase domain	kd	1.2000	uM
Quizartinib	507931: Binding affinity to EPHB6	kd	1.2000	uM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	507931: Binding affinity to EPHB6	kd	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases abundance, increases expression, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenate	increases abundance, decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
butyraldehyde	increases expression	1
ochratoxin A	increases expression, increases acetylation	1
ferrous chloride	decreases expression	1
nickel sulfate	increases expression	1
U 0126	increases expression	1
rofecoxib	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Folic Acid	affects expression	1

ChEMBL screening assays

87 unique, capped per target: 87 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1049969	Binding	Binding affinity to EPHB6 assessed as percentage of kinase remaining bound to the bead at 1 uM by T7 phage display based binding assay	Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM24	HAP1 EPHB6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00146497	PHASE4	TERMINATED	Cytokine Change in Bronchoalveolar Lavage Fluid After Early Budesonide-Surfactant Treatment in Premature Infants
NCT00277030	PHASE4	UNKNOWN	Two Strategies of RDS Treatment in Newborns With Birth Weight > 1500 Grams
NCT00295464	PHASE4	TERMINATED	Antenatal Rescue Course of Glucocorticoids in Threatened Premature Birth
NCT00368680	PHASE4	UNKNOWN	Early CPAP in Respiratory Distress Syndrome
NCT00391105	PHASE4	COMPLETED	Remifentanil Versus Morphine for Sedation of Premature Neonates With Respiratory Distress Syndrome
NCT00767039	PHASE4	TERMINATED	Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants
NCT00797160	PHASE4	UNKNOWN	Propofol Versus Midazolam as Premedication for Preterm Neonates With Respiratory Distress Syndrome (RDS)
NCT00883532	PHASE4	UNKNOWN	Prevention of Chronic Lung Disease (CLD) in Preterm Infants
NCT01374061	PHASE4	WITHDRAWN	Pre Hospital Evaluation of Video Laryngoscopy
NCT01749501	PHASE4	COMPLETED	Premedication for Non-Emergency Endotracheal Intubation In the NICU
NCT01923844	PHASE4	COMPLETED	Effects of Bolus Surfactant Therapy on Peripheral Perfusion Index and Tissue Carbon Monoxide
NCT02348047	PHASE4	TERMINATED	(S5-SAMU) Randomized Study Comparing the ASV (Adaptative Support Ventilation) to Conventional Ventilation
NCT02887924	PHASE4	UNKNOWN	SLI MANEUVER and RESPIRATORY MORBIDITIES
NCT02978976	PHASE4	UNKNOWN	Effect of Antenatal Steroid on Pulmonary Artery Blood Flow
NCT03275415	PHASE4	COMPLETED	Intratracheal Budesonide/Surfactant Prevents BPD
NCT03366584	PHASE4	UNKNOWN	The Effect of β-Carotene, Vitamin D3 and Zinc on Hyaline Membrane Disease and Feeding Intolerance in Premature Neonates
NCT03521063	PHASE4	UNKNOWN	Efficacy of Adding Budesonide to Poractant Alfa to Prevent Bronchopulmonary Dysplasia.
NCT04073173	PHASE4	UNKNOWN	Stress Assessment With and Without Analgesia During Surfactant Therapy in Preterm Infants.
NCT04199364	PHASE4	UNKNOWN	Medium vs Low Oxygen Threshold for the Surfactant Administration
NCT04334629	PHASE4	WITHDRAWN	LIBERATE Trial in COVID-19
NCT05714865	PHASE4	COMPLETED	Implementing LISA Surfactant in Nigeria
NCT05758597	PHASE4	UNKNOWN	Sedative Effect and Safety of Remimazolam Besylate in ARDS Patients
NCT06074380	PHASE4	RECRUITING	Non Inferiority Trial Investigating Surfactants Administered Via MIST
NCT06554522	PHASE4	RECRUITING	Pragmatic Evaluation of Respiratory Distress Syndrome Treatment in Africa
NCT07261787	PHASE4	RECRUITING	Duration of Surfactant Administration and Impact on Stabilisation of Vital Parameters in Very Preterm Neonates: 1 Minutes Versus 5 Minutes
NCT07350018	PHASE4	RECRUITING	Calfactant vs Poractant Alfa Using a Less Invasive Technique in Preterm Infants With Respiratory Distress Syndrome
NCT00000563	PHASE3	COMPLETED	Prevention of Neonatal Respiratory Distress Syndrome With Antenatal Steroid Administration
NCT00000567	PHASE3	COMPLETED	High Frequency Ventilation in Premature Infants (HIFI)
NCT00000570	PHASE3	COMPLETED	Human Surfactant Treatment of Respiratory Distress Syndrome Bicenter Trial
NCT00000576	PHASE3	COMPLETED	Inhaled Beclomethasone to Prevent Chronic Lung Disease
NCT00004778	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Antenatal Thyrotropin-Releasing Hormone in Pregnant Women With Threatened Premature Delivery
NCT00005774	PHASE3	TERMINATED	Early Surfactant to Reduce Use of Mechanical Breathing in Low Birth Weight Infants
NCT00005777	PHASE3	TERMINATED	Minimal Breathing Support and Early Steroids to Prevent Chronic Lung Disease in Extremely Premature Infants (SAVE)
NCT00016523	PHASE3	TERMINATED	Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure
NCT00356668	PHASE3	COMPLETED	Humidified High Flow Nasal Cannula as Compared to Nasal Continuous Positive Airway Pressure
NCT00563641	PHASE3	COMPLETED	Very Early Surfactant and NCPAP for Premature Infants With RDS
NCT01222247	PHASE3	COMPLETED	Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
NCT01265589	PHASE3	UNKNOWN	Intratracheal Vitamin A Administration With Surfactant for Newborn Respiratory Distress Syndrome
NCT01517828	PHASE3	UNKNOWN	Intranasal Midazolam Versus Intranasal Ketamine to Sedate Newborns for Intubation in Delivery Room
NCT01709409	PHASE3	COMPLETED	A Multi-center Trial to Determine if Curosurf® Reduces the Duration of Mechanical Ventilation in Very Preterm Infants