EPHA3

Summary

EPHA3 (EPH receptor A3, HGNC:3387) is a protein-coding gene on chromosome 3p11.1, encoding Ephrin type-A receptor 3 (P29320). Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 2042 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 109 total
• Druggable target: yes — 29 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 5 cancer types
• MANE Select transcript: NM_005233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3387
Approved symbol	EPHA3
Name	EPH receptor A3
Location	3p11.1
Locus type	gene with protein product
Status	Approved
Aliases	HEK, HEK4
Ensembl gene	ENSG00000044524
Ensembl biotype	protein_coding
OMIM	179611
Entrez	2042

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000336596, ENST00000452448, ENST00000494014, ENST00000860929, ENST00000860930, ENST00000860931, ENST00000934137

RefSeq mRNA: 3 — MANE Select: NM_005233 NM_001410778, NM_005233, NM_182644

CCDS: CCDS2922, CCDS46875, CCDS93324

Canonical transcript exons

ENST00000336596 — 17 exons

Exon	Start	End
ENSE00000774362	89341755	89342090
ENSE00000774379	89399318	89399480
ENSE00000774381	89407269	89407371
ENSE00000774382	89408067	89408131
ENSE00000774383	89413141	89413266
ENSE00000774387	89419205	89419390
ENSE00000774392	89429106	89429167
ENSE00000774396	89431150	89431359
ENSE00001000999	89395837	89395961
ENSE00001142467	89472464	89472619
ENSE00001142474	89450177	89450370
ENSE00001157881	89340916	89341071
ENSE00001309114	89127209	89127273
ENSE00001329887	89209860	89210520
ENSE00001330937	89107621	89107836
ENSE00001353258	89479397	89482134
ENSE00002376868	89449225	89449374

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 95.63.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4389 / max 492.9646, expressed in 649 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37466	3.1484	554
37468	1.7550	422
37467	1.2956	391
37469	0.1946	77
37470	0.0453	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	95.63	gold quality
buccal mucosa cell	CL:0002336	94.14	gold quality
urethra	UBERON:0000057	93.78	gold quality
gall bladder	UBERON:0002110	86.13	gold quality
mucosa of urinary bladder	UBERON:0001259	85.25	gold quality
cortical plate	UBERON:0005343	84.92	gold quality
tibia	UBERON:0000979	83.06	gold quality
calcaneal tendon	UBERON:0003701	83.06	gold quality
embryo	UBERON:0000922	82.78	gold quality
prostate gland	UBERON:0002367	82.75	gold quality
urinary bladder	UBERON:0001255	82.62	gold quality
right coronary artery	UBERON:0001625	81.04	gold quality
placenta	UBERON:0001987	80.59	gold quality
thyroid gland	UBERON:0002046	80.11	gold quality
visceral pleura	UBERON:0002401	79.88	gold quality
seminal vesicle	UBERON:0000998	79.77	gold quality
heart right ventricle	UBERON:0002080	79.54	gold quality
left lobe of thyroid gland	UBERON:0001120	79.50	gold quality
layer of synovial tissue	UBERON:0007616	78.44	gold quality
tibial artery	UBERON:0007610	78.06	gold quality
popliteal artery	UBERON:0002250	78.03	gold quality
left coronary artery	UBERON:0001626	77.81	gold quality
colonic epithelium	UBERON:0000397	77.80	gold quality
right lobe of thyroid gland	UBERON:0001119	77.80	gold quality
rectum	UBERON:0001052	77.56	gold quality
coronary artery	UBERON:0001621	77.13	gold quality
mammalian vulva	UBERON:0000997	76.87	gold quality
tendon	UBERON:0000043	76.28	gold quality
cardiac muscle of right atrium	UBERON:0003379	76.03	gold quality
smooth muscle tissue	UBERON:0001135	75.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA13, HOXD13, OLIG2, RBPJ, TLE5

miRNA regulators (miRDB)

183 targeting EPHA3, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 40)

• EphA3, was identified as a new CD28-responsive gene in Jurkat cells by using a human cytokine/receptor array. EphA3 expression in CD28-stimulated Jurkat cells was enhanced by IGF-1 or by overexpression of the IGF-1R. (PMID:14697337)
• Results show EPHA3 gene was implicated in the pathogenesis of lung cancer and it may be useful targets for diagnostic and therapeutic intervention in selected patients. (PMID:16941478)
• ephrin-A5-induced cell-morphologic changes of EphA3-positive LK63 pre-B acute lymphoblastic leukemia cells (PMID:18385452)
• High-resolution structures of the EphA3 kinase with and without the juxtamembrane segment allowed mapping of the coupled pathway of residues that connect the juxtamembrane segment, the activation loop, and the catalytic residues of the kinase domain. (PMID:18547520)
• EphA3 expression may define subsets of rhabdomyosarcoma tumours, and that EphA3 suppresses motility through regulation of Rho GTPases in rhabdomyosarcoma cells. (PMID:18814179)
• D219V missense mutation in EPHA3 is associated with hepatocellular carcinoma. (PMID:19469653)
• mechanism of substrate binding (PMID:19678838)
• Data provide further support that ALS2CL, EPHA3, and CMYA1 are bona-fide tumor-suppressor genes and contribute to the tumorigenesis of HNSCC. (PMID:20657180)
• Data shew that the identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. (PMID:21124932)
• Experiments in EphA3/Isl2 knock-in mice test the interactions between effects of molecular labels and correlated activity during the development of neural connectivity. (PMID:21190559)
• expression of EphA3 and CD133 in carcinoma was significantly higher than that in normal mucosal tissue (PMID:21415057)
• Authors found significant association between the copy number variations of EphA3 and hematologic malignancies. (PMID:21454190)
• EphA3 has ephrin- and kinase-dependent tumor suppressing activities, which are disrupted by somatic cancer mutations (PMID:22242939)
• EphA3 may play important roles in the angiogenesis and prognosis of gastric carcinoma (PMID:22350700)
• Cancer-associated EPHA3 mutations attenuate the tumor-suppressive effects of normal EPHA3 in lung cancer. (PMID:22829656)
• EPHA3 mutations may promote tumorigenesis only when key senescence-inducing pathways have been inactivated. (PMID:23324396)
• High EphA3 expression is associated with glioblastoma multiforme. (PMID:23410976)
• EphA3 may represent a novel candidate marker for patient prognosis as well a molecular target for HCC therapy. (PMID:23970317)
• Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions (PMID:23991104)
• EphA3 was induced by PC-1 and contributed to the malignant progression of prostate cancer (PMID:25231727)
• Data indicate that hypoxia increased EphA3 receptor (EphA3) mRNA expression in EphA3+ endometrial multipotent mesenchymal stromal cells (eMSCs). (PMID:25420155)
• the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5, is reported. (PMID:25993310)
• EphA3 forms dimers in the absence of ligand binding. (PMID:26232493)
• This study showed that EPHA3 gene involved in neuronal growth and cerebellum development and associated with neurological and psychological disorders. (PMID:26381449)
• A novel association between the EPHA3 deletion and prostate cancer risk was observed in Finnish individuals. (PMID:26552734)
• PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and through its direct action as a PTP controlling EphA3 phosphorylation. (PMID:26644181)
• Data indicate that EPHA3 is involved in regulating the multidrug resistance (MDR) of small cell lung cancer (SCLC) via PI3K/BMX/STAT3 signaling and may be a therapeutic target in SCLC. (PMID:27101199)
• Results indicate that EphA3 protein expression is reduced in clear-cell renal cell carcinoma, suggesting the possibility that this receptor functions as a tumor suppressor in this disease. (PMID:27591824)
• EphA3 promotes malignant transformation of colorectal epithelial cells by upregulating oncogenic signaling pathways. (PMID:27721017)
• Although EPHA3 was reported to be one of the most frequently mutated genes in colorectal tumors, our studies using inducible isogenic cell line systems, mouse models and large human tumor collections, did not reveal a major role of this EPH receptor on proliferation/motility/invasion of cancer cells, tumor initiation/progression/metastasis in mouse models or survival of colorectal cancer patients. (PMID:28169277)
• Study shows that EphA3 is highly overexpressed in multiple myeloma (MM) and provides evidence that EphA3 plays an important role in MM angiogenesis. (PMID:28415715)
• Findings suggest that EPH receptor A3 (EphA3) plays an important role in the pathogenesis of multiple myeloma (MM). (PMID:28721629)
• EphA3 mediated the tumor invasiveness and migration in radioresistant head and neck cancer cell lines and epithelial mesenchymal transition- related protein expression. Inhibition of EphA3 enhanced radiosensitivity in the AMC HN 3R cell line in vitro and in vivo study. (PMID:29653204)
• EphA3 is a target of miR-340, and ectopic expression of EphA3 can promote the migration and invasion of cervical cancer cells, whereas restoration of EphA3 in miR-340-overexpressing cervical cancer cells reversed the suppressive effects of miR-340. (PMID:29660208)
• The interaction of AR and SP1 contributes to regulate EPHA3 expression. (PMID:29917167)
• To investigate the relationship between five EPHA3 single nucleotide polymorphisms (SNPs) and Nonsyndromic Cleft Lip With or Without Cleft Palate (NSCL/P), EPHA3 SNPs (rs7650466, rs1398197, rs17801309, rs1054750, and rs7632427) were genotyped. The rs7650466 T allele was associated with the incidence of NSCL/P as well as with protective and dominant effects in both conditions. (PMID:29932736)
• we show that EPHA2 and EPHA3 together mark a GBM stem cells (GSC) population in treatment-refractory, recurrent Glioblastoma (rGBM) and that strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM. (PMID:29945963)
• High EPHA3 expression is associated with tumor growth and angiogenesis in gastric cancer. (PMID:30066881)
• silencing EphA3 in KYSE410 cells triggered epithelialmesenchymal transition, and promoted cell migration and invasion. These results suggested that EphA3 may serve a tumorsuppressor role in esophageal squamous cell carcinoma. (PMID:30483759)
• the regulation of EphA3 expression plays a critical role in glioblastoma cell growth in non-adherent conditions. (PMID:30528229)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	epha3l	ENSDARG00000039373
mus_musculus	Epha3	ENSMUSG00000052504
rattus_norvegicus	Epha3	ENSRNOG00000030285

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Ephrin type-A receptor 3 — P29320 (reviewed: P29320)

Alternative names: EPH-like kinase 4, HEK, Tyrosine-protein kinase TYRO4, Tyrosine-protein kinase receptor ETK1

All UniProt accessions (3): A0A140VJJ0, C9JXA2, P29320

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin 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. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Also activated by EFNA1, inhibiting epithelial-to-mesenchymal transition of cardiac cells and playing a role in heart development. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.

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. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function. Interacts with NCK1 (via SH2 domain); mediates EFNA5-EPHA3 signaling. Interacts (phosphorylated) with PTPN1; dephosphorylates EPHA3 and may regulate its trafficking and function. Interacts (phosphorylated) with CRK; mediates EFNA5-EPHA3 signaling through RHOA GTPase activation.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Widely expressed. Highest level in placenta.

Post-translational modifications. Autophosphorylates upon activation by EFNA5. Phosphorylation on Tyr-602 mediates interaction with NCK1. Dephosphorylated by PTPN1.

Disease relevance. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The gene represented in this entry may be involved in disease pathogenesis.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P29320-1	1	yes
P29320-2	2

RefSeq proteins (3): NP_001397707, NP_005224, NP_872585 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001090	EPH_LBD	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001426	Tyr_kinase_rcpt_V_CS	Conserved_site
IPR001660	SAM	Domain
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011641	Tyr-kin_ephrin_A/B_rcpt-like	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016257	EPH	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR027936	EPH_TM	Domain
IPR034266	EphA3_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF01404, PF07647, 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 (96 total): strand 22, sequence variant 17, helix 17, mutagenesis site 6, modified residue 5, glycosylation site 5, domain 5, turn 5, binding site 4, topological domain 2, splice variant 2, signal peptide 1, chain 1, short sequence motif 1, active site 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
2QOL	X-RAY DIFFRACTION	1.07
2QOD	X-RAY DIFFRACTION	1.15
2QOF	X-RAY DIFFRACTION	1.2
2QOK	X-RAY DIFFRACTION	1.2
2QOC	X-RAY DIFFRACTION	1.25
2QOI	X-RAY DIFFRACTION	1.25
2QOO	X-RAY DIFFRACTION	1.25
4P5Q	X-RAY DIFFRACTION	1.35
6IN0	X-RAY DIFFRACTION	1.5
2QO9	X-RAY DIFFRACTION	1.55
4P4C	X-RAY DIFFRACTION	1.6
2QO2	X-RAY DIFFRACTION	1.6
2QOQ	X-RAY DIFFRACTION	1.6
2QO7	X-RAY DIFFRACTION	1.6
2QOB	X-RAY DIFFRACTION	1.65
4G2F	X-RAY DIFFRACTION	1.7
3FXX	X-RAY DIFFRACTION	1.7
4TWN	X-RAY DIFFRACTION	1.71
3DZQ	X-RAY DIFFRACTION	1.75
2GSF	X-RAY DIFFRACTION	1.77
2QON	X-RAY DIFFRACTION	1.79
3FY2	X-RAY DIFFRACTION	1.8
4GK3	X-RAY DIFFRACTION	1.9
4P5Z	X-RAY DIFFRACTION	2
4TWO	X-RAY DIFFRACTION	2.05
4GK4	X-RAY DIFFRACTION	2.1
4GK2	X-RAY DIFFRACTION	2.19
4L0P	X-RAY DIFFRACTION	2.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29320-F1	81.22	0.54

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): 746 (proton acceptor)

Ligand- & substrate-binding residues (4): 628–633; 653; 700–706; 750–751

Post-translational modifications (5): 596, 602, 701, 779, 937

Glycosylation sites (5): 232, 337, 391, 404, 493

Mutagenesis-validated functional residues (6):

Position	Phenotype
133	loss of efna5-binding ability and function.
152	loss of efna5-binding ability and function.
596	10-fold suppression of kinase activity; when associated with f-602. full kinase activity; when associated with f-602 and
602	10-fold suppression of kinase activity; when associated with f-596. full kinase activity; when associated with f-596 and
742	full kinase activity; when associated with f-596 and f-602.
768	full kinase activity; when associated with f-596 and f-602.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928663	EPHA-mediated growth cone collapse
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 315 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEURON_RECOGNITION, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_CELLULAR_RESPONSE_TO_LIPID, ATACCTC_MIR202, GOZGIT_ESR1_TARGETS_DN, GOBP_FOCAL_ADHESION_ASSEMBLY, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (20): cell adhesion (GO:0007155), axon guidance (GO:0007411), regulation of epithelial to mesenchymal transition (GO:0010717), negative regulation of epithelial to mesenchymal transition (GO:0010719), positive regulation of neuron projection development (GO:0010976), cell migration (GO:0016477), peptidyl-tyrosine phosphorylation (GO:0018108), regulation of cell-cell adhesion (GO:0022407), regulation of actin cytoskeleton organization (GO:0032956), regulation of GTPase activity (GO:0043087), negative regulation of endocytosis (GO:0045806), ephrin receptor signaling pathway (GO:0048013), regulation of focal adhesion assembly (GO:0051893), regulation of microtubule cytoskeleton organization (GO:0070507), cellular response to retinoic acid (GO:0071300), fasciculation of sensory neuron axon (GO:0097155), fasciculation of motor neuron axon (GO:0097156), positive regulation of protein localization to plasma membrane (GO:1903078), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169)

GO Molecular Function (11): ephrin receptor activity (GO:0005003), GPI-linked ephrin receptor activity (GO:0005004), transmembrane-ephrin receptor activity (GO:0005005), ATP binding (GO:0005524), 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 (9): extracellular region (GO:0005576), nucleoplasm (GO:0005654), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), dendrite (GO:0030425), nuclear membrane (GO:0031965), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	2
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
epithelial to mesenchymal transition	2
regulation of cytoskeleton organization	2
axonal fasciculation	2
ephrin receptor activity	2
cellular process	1
axonogenesis	1
neuron projection guidance	1
regulation of cell differentiation	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell motility	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
regulation of cell adhesion	1
cell-cell adhesion	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
GTPase activity	1
regulation of hydrolase activity	1
endocytosis	1
regulation of endocytosis	1
negative regulation of transport	1
negative regulation of cellular component organization	1
cell surface receptor protein tyrosine kinase signaling pathway	1
regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of cell-substrate junction assembly	1
microtubule cytoskeleton organization	1
regulation of microtubule-based process	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1

Protein interactions and networks

STRING

2244 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHA3	EFNA5	P52803	997
EPHA3	EFNA2	O43921	979
EPHA3	EFNB2	P52799	968
EPHA3	EFNA1	P20827	948
EPHA3	EFNA3	P52797	939
EPHA3	RUFY2	Q8WXA3	884
EPHA3	EFNA4	P52798	871
EPHA3	EFNB3	Q15768	834
EPHA3	RUFY1	Q96T51	763
EPHA3	EPHA5	P54756	758
EPHA3	EPHA4	P54764	691
EPHA3	EFNB1	P98172	621
EPHA3	KDR	P35968	564
EPHA3	CACNB4	O00305	551
EPHA3	PIK3CA	P42336	546

IntAct

66 interactions, top by confidence:

A	B	Type	Score
CHUK	IKBKB	psi-mi:“MI:0914”(association)	0.960
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
EPHA3	EPHA7	psi-mi:“MI:0407”(direct interaction)	0.670
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
	EPHA3	psi-mi:“MI:0407”(direct interaction)	0.560
EPHA3		psi-mi:“MI:0407”(direct interaction)	0.560
EPHA3		psi-mi:“MI:0217”(phosphorylation reaction)	0.560
	EPHA3	psi-mi:“MI:0217”(phosphorylation reaction)	0.560
EPHA3	SMAD4	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	EPHA3	psi-mi:“MI:2364”(proximity)	0.550
SMAD4	EPHA3	psi-mi:“MI:0915”(physical association)	0.550
EPHA3	EPHA2	psi-mi:“MI:0915”(physical association)	0.540
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SRPK1	EPHA3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EPHA3	H1-2	psi-mi:“MI:0915”(physical association)	0.400
EPHA3	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
ILKAP	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
CTDSP2	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
DUSP18	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
DUSP21	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
STYX	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
TPTE	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
MTMR11	EPHA3	psi-mi:“MI:0915”(physical association)	0.370
EPHA3	RBM18	psi-mi:“MI:0915”(physical association)	0.370
CDKN2A	ACTN4	psi-mi:“MI:0914”(association)	0.350

BioGRID (145): EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), EPHA3 (Affinity Capture-MS), ILKAP (Two-hybrid), CTDSP2 (Two-hybrid), DUSP18 (Two-hybrid), DUSP21 (Two-hybrid), STYX (Two-hybrid)

ESM2 similar proteins: A1XQX0, A1XQX2, A1XQX8, A1XQY1, A3KN33, B4F785, B8UU78, D0PRN3, E9Q7X7, P12080, P29319, P29320, P54764, Q02763, Q02858, Q03137, Q06807, Q07310, Q07496, Q0V8S9, Q0V8T0, Q0V8T3, Q0V8T4, Q0V8T5, Q0V8T6, Q0V8T7, Q0V8T8, Q0V8T9, Q19617, Q28146, Q3KN41, Q4VBE4, Q5RD64, Q63372, Q63374, Q63HQ2, Q6P9K9, Q8QFX6, Q8WYK1, Q91694

Diamond homologs: A2A863, A5Z1X6, B0FYY4, O08680, O54890, O70309, P05106, P05107, P05556, P07228, P09055, P11584, P11835, P12606, P12607, P16144, P18084, P18563, P18564, P26010, P26011, P26012, P29319, P29320, P32592, P49134, P53712, P53713, P53714, P80747, Q07409, Q07441, Q09062, Q0VBD0, Q1RPR6, Q27591, Q27874, Q2VJ42, Q3UH53, Q3UV74

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
EPHA3	up-regulates	CRK	binding
PTPN1	“down-regulates activity”	EPHA3	dephosphorylation
EPHA3	“up-regulates activity”	EPHA3	phosphorylation
EPHA3	“up-regulates activity”	PAK1	phosphorylation
EPHA3	“up-regulates activity”	AR	phosphorylation
EPHA3	“up-regulates activity”	UXS1	phosphorylation
EFNA1	up-regulates	EPHA3	binding
EFNA3	up-regulates	EPHA3	binding
EFNA5	up-regulates	EPHA3	binding
EPHA3	up-regulates	SRC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
NCAM signaling for neurite out-growth	5	34.0×	2e-05
EPH-ephrin mediated repulsion of cells	5	27.4×	4e-05
EPH-Ephrin signaling	5	20.7×	1e-04
Downstream TCR signaling	6	19.2×	3e-05
RAF/MAP kinase cascade	5	7.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	31.3×	4e-04
Ras protein signal transduction	5	18.7×	3e-03
protein stabilization	6	7.3×	9e-03
immune response	7	6.0×	9e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 5 cancer types — BRCA, ESCA, MEL, PRAD, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4215 predictions. Top by Δscore:

Variant	Effect	Δscore
3:89127207:A:AG	acceptor_gain	1.0000
3:89127208:G:GG	acceptor_gain	1.0000
3:89209849:T:A	acceptor_gain	1.0000
3:89209855:TTCAG:T	acceptor_loss	1.0000
3:89209857:CAG:C	acceptor_loss	1.0000
3:89209858:A:AG	acceptor_gain	1.0000
3:89209858:AGT:A	acceptor_gain	1.0000
3:89209858:AGTG:A	acceptor_gain	1.0000
3:89209858:AGTGG:A	acceptor_gain	1.0000
3:89209859:G:GT	acceptor_gain	1.0000
3:89209859:GT:G	acceptor_gain	1.0000
3:89209859:GTG:G	acceptor_gain	1.0000
3:89209859:GTGG:G	acceptor_gain	1.0000
3:89209859:GTGGG:G	acceptor_gain	1.0000
3:89210519:AGG:A	donor_loss	1.0000
3:89210521:G:GA	donor_loss	1.0000
3:89210522:T:G	donor_loss	1.0000
3:89340914:A:AG	acceptor_gain	1.0000
3:89340915:G:GA	acceptor_gain	1.0000
3:89340915:GCTT:G	acceptor_gain	1.0000
3:89341072:G:GG	donor_gain	1.0000
3:89342086:GGCTG:G	donor_gain	1.0000
3:89342087:GCTG:G	donor_gain	1.0000
3:89342087:GCTGG:G	donor_gain	1.0000
3:89342089:TG:T	donor_gain	1.0000
3:89342090:GG:G	donor_gain	1.0000
3:89342091:G:C	donor_loss	1.0000
3:89342091:G:GG	donor_gain	1.0000
3:89342092:T:G	donor_loss	1.0000
3:89395832:TACA:T	acceptor_loss	1.0000

AlphaMissense

6506 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:89127250:T:A	W44R	1.000
3:89127250:T:C	W44R	1.000
3:89127252:G:C	W44C	1.000
3:89127252:G:T	W44C	1.000
3:89209860:T:A	W52R	1.000
3:89209860:T:C	W52R	1.000
3:89209861:G:C	W52S	1.000
3:89209862:G:C	W52C	1.000
3:89209862:G:T	W52C	1.000
3:89209917:T:A	C71S	1.000
3:89209917:T:C	C71R	1.000
3:89209918:G:A	C71Y	1.000
3:89209918:G:C	C71S	1.000
3:89209919:C:G	C71W	1.000
3:89209951:T:C	L82P	1.000
3:89210002:T:C	L99P	1.000
3:89210007:T:C	F101L	1.000
3:89210008:T:C	F101S	1.000
3:89210008:T:G	F101C	1.000
3:89210009:C:A	F101L	1.000
3:89210009:C:G	F101L	1.000
3:89210014:T:C	L103P	1.000
3:89210017:G:C	R104P	1.000
3:89210022:T:A	C106S	1.000
3:89210022:T:C	C106R	1.000
3:89210023:G:A	C106Y	1.000
3:89210023:G:C	C106S	1.000
3:89210024:C:G	C106W	1.000
3:89210052:T:A	C116S	1.000
3:89210052:T:C	C116R	1.000

dbSNP variants (sampled 300 via entrez): RS1000025889 (3:89364986 C>T), RS1000031174 (3:89394664 A>G), RS1000038396 (3:89292155 A>G), RS1000044234 (3:89253736 T>A), RS1000061043 (3:89166406 G>A), RS1000088903 (3:89292539 T>C), RS1000093380 (3:89166633 C>A), RS1000106221 (3:89124844 T>A,C), RS1000111144 (3:89290628 T>C), RS1000129629 (3:89317507 T>A), RS1000146300 (3:89246651 T>C), RS1000159591 (3:89206926 C>T), RS1000178538 (3:89247073 A>G), RS1000180204 (3:89317128 T>A,C), RS1000184718 (3:89326545 A>G)

Disease associations

OMIM: gene MIM:179611 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001628_28	Orofacial clefts	4.000000e-08
GCST002127_16	Periodontitis (Mean PAL)	2.000000e-06
GCST003390_11	Thrombosis	8.000000e-07
GCST003773_2	Loneliness (multivariate analysis)	7.000000e-06
GCST004495_28	BMI (adjusted for smoking behaviour)	8.000000e-08
GCST004495_29	BMI (adjusted for smoking behaviour)	2.000000e-09
GCST004497_125	Body mass index (joint analysis main effects and smoking interaction)	3.000000e-07
GCST004497_130	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-07
GCST004499_24	BMI in non-smokers	7.000000e-07
GCST004499_25	BMI in non-smokers	4.000000e-07
GCST005752_23	Systemic lupus erythematosus	5.000000e-07
GCST006061_73	Atrial fibrillation	1.000000e-08
GCST006061_74	Atrial fibrillation	2.000000e-09
GCST006414_79	Atrial fibrillation	2.000000e-11
GCST007094_110	Diastolic blood pressure	1.000000e-07
GCST007098_49	Diastolic blood pressure	1.000000e-08
GCST007099_5	Systolic blood pressure	4.000000e-06
GCST008273_1	Post-bronchodilator FEV1 x air pollution (NO2) interaction in childhood asthma	1.000000e-06
GCST008482_3	Lung function (FVC)	2.000000e-06
GCST008529_10	Tea consumption	1.000000e-09
GCST009724_32	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-13
GCST010698_29	Subcortical volume (min-P)	3.000000e-08
GCST010699_111	Brain morphology (min-P)	4.000000e-08
GCST010701_130	Cortical surface area (MOSTest)	2.000000e-10
GCST010702_130	Subcortical volume (MOSTest)	3.000000e-15
GCST010703_97	Brain morphology (MOSTest)	1.000000e-42
GCST010988_106	Adult body size	5.000000e-12
GCST011124_16	Caffeine consumption from tea	3.000000e-09
GCST012008_2	Lateral thalamic nuclei volume	7.000000e-09
GCST012011_5	Ventral thalamic nuclei volume	7.000000e-11

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0003907	deep vein thrombosis
EFO:0007865	loneliness measurement
EFO:0004318	smoking behavior
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004314	forced expiratory volume
EFO:0007908	traffic air pollution measurement
EFO:0004312	vital capacity
EFO:0010091	tea consumption measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0004346	neuroimaging measurement
EFO:0006935	thalamus volume
EFO:0004338	body weight
EFO:0007797	language measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL4954 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

29 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 634,140 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
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
CHEMBL939	GEFITINIB	4	117,814
CHEMBL1908391	MASITINIB	3	2,808
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL475251	R-406	2
CHEMBL572878	TOZASERTIB	2
CHEMBL607707	PELITINIB	2
CHEMBL1908397	KW-2449	1
CHEMBL259084	MLN-8054	1
CHEMBL574738	AST-487	1

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

GtoPdb / IUPHAR curated pharmacology

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

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

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

Ligand	Action	Affinity	Parameter
fibatuzumab	Binding	9.0	pKd
sitravatinib	Inhibition	9.0	pIC50
compound 8h [PMID: 21561767]	Inhibition	8.92	pIC50
compound 66 [PMID: 19788238]	Inhibition	7.4	pIC50
compound 20 [PMID: 23489211]	Inhibition	5.6	pIC50

Binding affinities (BindingDB)

16 measured of 18 human assays (18 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
3-[[2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridin-7-yl]amino]phenol	IC50	5.1 nM	US-9062066: Anti-inflammatory compound having inhibitory activity against multiple tyrosine kinases and pharmaceutical composition containing same
BMS-354825	KD	27 nM
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 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
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM
123C4	KI	640 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
CI-1033	KD	1700 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

102 potent at pChembl≥5 of 102 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.03	Kd	0.093	nM	DASATINIB
10.00	Kd	0.1	nM	CHEMBL249097
9.52	IC50	0.3	nM	CHEMBL3752910
9.52	IC50	0.3	nM	DASATINIB ANHYDROUS
9.00	Kd	1	nM	FORETINIB
8.92	IC50	1.2	nM	CHEMBL1784637
8.70	EC50	2	nM	CHEMBL459850
8.29	IC50	5.1	nM	CHEMBL2336005
8.24	Kd	5.8	nM	BOSUTINIB
8.12	Kd	7.6	nM	CHEMBL386051
8.07	Kd	8.58	nM	CHEMBL3321809
7.71	IC50	19.72	nM	STAUROSPORINE
7.66	IC50	22	nM	CHEMBL4568087
7.64	Kd	23	nM	CHEMBL5415503
7.57	Kd	27	nM	STAUROSPORINE
7.52	IC50	29.9	nM	STAUROSPORINE
7.50	IC50	31.9	nM	STAUROSPORINE
7.41	Kd	39.3	nM	CHEMBL3321822
7.41	IC50	39	nM	STAUROSPORINE
7.40	IC50	40	nM	CHEMBL566515
7.34	Kd	46	nM	CHEMBL515466
7.32	IC50	48	nM	STAUROSPORINE
7.30	IC50	50	nM	CHEMBL5653589
7.28	IC50	52	nM	CHEMBL4550702
7.26	Kd	55	nM	STAUROSPORINE
7.10	Kd	80	nM	AST-487
6.96	Kd	110	nM	NILOTINIB
6.80	Kd	160	nM	LESTAURTINIB
6.75	IC50	180	nM	CHEMBL4569508
6.60	Kd	250	nM	CHEMBL5172097
6.44	Kd	360	nM	R-406
6.41	Kd	390	nM	CHEMBL1241674
6.26	IC50	552	nM	CHEMBL4793380
6.24	Kd	580	nM	DORAMAPIMOD
6.19	Kd	650	nM	CANERTINIB
6.16	Kd	700	nM	CRIZOTINIB
6.13	Kd	747	nM	CHEMBL4465866
6.09	Kd	810	nM	KW-2449
6.06	Kd	880	nM	DORAMAPIMOD
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.92	IC50	1200	nM	DORAMAPIMOD
5.82	Kd	1500	nM	CHEMBL4878061
5.82	Kd	1500	nM	TOZASERTIB
5.80	IC50	1600	nM	CHEMBL2070045
5.80	Kd	1600	nM	CHEMBL1908395
5.75	Kd	1800	nM	VANDETANIB
5.72	Kd	1900	nM	SORAFENIB
5.70	Kd	2000	nM	VANDETANIB

PubChem BioAssay actives

99 with measured affinity, of 785 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	435794: Binding constant for EPHA3 kinase domain	kd	0.0001	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389071: Binding affinity to human EPHA3	kd	0.0001	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147741: Inhibition of Nano Luc-fused full length C-terminal EPHA3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0003	uM
Dasatinib	2147741: Inhibition of Nano Luc-fused full length C-terminal EPHA3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0003	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	625009: Binding constant for EPHA3 kinase domain	kd	0.0010	uM
5-[2-[5-[[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-2-methylphenyl]ethynyl]-N,1-dimethylimidazole-2-carboxamide	601672: Inhibition of human EPHA3 using poly[Glu:Tyr] peptide substrate by Hotspot assay	ic50	0.0012	uM
N-[3-(7-amino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	383085: Inhibition of EphA3 by cellular assay	ec50	0.0020	uM
Bosutinib	625009: Binding constant for EPHA3 kinase domain	kd	0.0058	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	625009: Binding constant for EPHA3 kinase domain	kd	0.0076	uM
2-amino-1-(5-hydroxy-2-methylphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide	1186107: Binding affinity to EphA3 (unknown origin) by surface plasmon resonance	kd	0.0086	uM
N-[3-[2-[4-(2-aminoethoxy)anilino]quinazolin-6-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1799897: Fluorescence Assay from Article 10.1021/cb300623a: “A Hexylchloride-Based Catch-and-Release System for Chemical Proteomic Applications.”	ic50	0.0100	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	1350966: Inhibition of EPHA3 (unknown origin)	ic50	0.0197	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637073: Inhibition of recombinant human His-tagged cytoplasmic EPHA3 expressed in baculovirus expression system by LanthaScreen assay	ic50	0.0220	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	1988534: Binding affinity to EPHA3 (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0230	uM
N-[3-[[3-[4-[4-[2-[5-[3-(2-fluoro-10,12-dimethyl-1-aza-3-azonia-2-boratricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)propanoylamino]pentanoylamino]ethoxy]anilino]-1,3,5-triazin-2-yl]-2-pyridinyl]amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1799543: In Vitro Activity Assay from Article 10.1016/j.chembiol.2010.01.008: “Affinity reagents that target a specific inactive form of protein kinases.”	kd	0.0270	uM
2-amino-1-[4-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrrolo[3,2-b]quinoxaline-3-carboxamide	1186107: Binding affinity to EphA3 (unknown origin) by surface plasmon resonance	kd	0.0393	uM
7-(5-hydroxy-2-methylphenyl)-6-(2-methoxyphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione	441387: Inhibition of EphA3 by [gamma33-P]ATP based assay	ic50	0.0400	uM
N-(3-tert-butylphenyl)-3-[4-(cyclopropylmethylcarbamoyl)phenyl]-4-methylbenzamide	389071: Binding affinity to human EPHA3	kd	0.0460	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147741: Inhibition of Nano Luc-fused full length C-terminal EPHA3 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0500	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637073: Inhibition of recombinant human His-tagged cytoplasmic EPHA3 expressed in baculovirus expression system by LanthaScreen assay	ic50	0.0520	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435794: Binding constant for EPHA3 kinase domain	kd	0.0800	uM
Nilotinib	625009: Binding constant for EPHA3 kinase domain	kd	0.1100	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	507921: Binding affinity to EPHA3	kd	0.1600	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637073: Inhibition of recombinant human His-tagged cytoplasmic EPHA3 expressed in baculovirus expression system by LanthaScreen assay	ic50	0.1800	uM
(4S)-5-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyloxy]-4-[[2-[3-[2-[[3-[2-[[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[(2-aminoacetyl)amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]methoxy]ethoxy]propanoylamino]methoxy]ethoxy]propanoylamino]-6-[3-[2-[[3-[2-[[[2-[[2-[[2-[3-[4-[3-[4-amino-3-(4-chlorophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]phenyl]triazol-1-yl]propylamino]acetyl]amino]acetyl]amino]acetyl]amino]methoxy]ethoxy]propanoylamino]methoxy]ethoxy]propanoylamino]hexanoyl]amino]-5-oxopentanoic acid	1846290: Inhibition of EPHA3 (unknown origin) assessed as dissociation constant by ELISA-like binding assay	kd	0.2500	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	625009: Binding constant for EPHA3 kinase domain	kd	0.3600	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625009: Binding constant for EPHA3 kinase domain	kd	0.3900	uM
N-[5-[[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-2-methylphenyl]-5-thiophen-2-ylpyridine-3-carboxamide	432914: Inhibition of Tel fused EphA3 expressed in mouse BA/F3 cells	ec50	0.5000	uM
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-(6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-ylamino)phenyl]urea	1735625: Inhibition of recombinant human EphA3 (578 to end residues) using poly(Glu, Tyr) 4:1 as substrate incubated for 40 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.5520	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	256601: Average Binding Constant for EPHA3; NA=Not Active at 10 uM	kd	0.5800	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	256601: Average Binding Constant for EPHA3; NA=Not Active at 10 uM	kd	0.6500	uM
Crizotinib	625009: Binding constant for EPHA3 kinase domain	kd	0.7000	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	1526134: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged EPHA3 (unknown origin) (579 to 983 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.7470	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625009: Binding constant for EPHA3 kinase domain	kd	0.8100	uM
(4S,7R,10S,13R,20S,23R,26R,29R)-29-[[(2S)-2-[[(2R)-1-(3-aminopropanoyl)pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-20-[3-(diaminomethylideneamino)propyl]-7,13-bis(hydroxymethyl)-23-[(4-hydroxyphenyl)methyl]-10-(1H-indol-3-ylmethyl)-6,9,12,15,19,22,25,28-octaoxo-26-propan-2-yl-1,2-dithia-5,8,11,14,18,21,24,27-octazacyclotriacontane-4-carboxamide	1765938: Binding affinity to N-terminal His tagged EphA3 LBD (unknown origin) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	1.5000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435794: Binding constant for EPHA3 kinase domain	kd	1.5000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625009: Binding constant for EPHA3 kinase domain	kd	1.6000	uM
3-(6-methoxynaphthalen-2-yl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-amine;hydrochloride	677068: Inhibition of human EPHA3 using myelin basic protein as substrate after 120 mins	ic50	1.6000	uM
Vandetanib	256601: Average Binding Constant for EPHA3; NA=Not Active at 10 uM	kd	1.8000	uM
Sorafenib	435794: Binding constant for EPHA3 kinase domain	kd	1.9000	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336043: Inhibition of human recombinant His-tagged EPHA3 cytoplasmic domain (569 to 976 residues) expressed in baculovirus expression system	ic50	2.0940	uM
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	435794: Binding constant for EPHA3 kinase domain	kd	2.1000	uM
8-(4-aminobutyl)-6-(2,5-difluorophenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974631: Inhibition of full length NanoLuc fused EPHA3 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	2.1000	uM
Sunitinib	435794: Binding constant for EPHA3 kinase domain	kd	2.1000	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	625009: Binding constant for EPHA3 kinase domain	kd	2.3000	uM
Erlotinib	435794: Binding constant for EPHA3 kinase domain	kd	2.4000	uM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide	625009: Binding constant for EPHA3 kinase domain	kd	2.5000	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	728717: Displacement of ephrin-A1-Fc from EphA3 receptor Fc ectodomain (unknown origin) after 1 hr by ELISA	ic50	2.5000	uM
1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)-3-pyridinyl]naphthalen-1-yl]urea	353510: Inhibition of HEK	ic50	3.2000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	435794: Binding constant for EPHA3 kinase domain	kd	3.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	4
Valproic Acid	decreases expression, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression	3
ponatinib	decreases activity	2
Panobinostat	increases expression, affects cotreatment	2
Doxorubicin	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
rofecoxib	decreases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
belinostat	increases expression	1
4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
licochalcone B	decreases expression	1
picoxystrobin	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Aldrin	affects cotreatment, increases expression	1
Antimycin A	decreases expression	1
Hexachlorocyclohexane	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases expression	1
Dichlorodiphenyldichloroethane	affects cotreatment, increases expression	1

ChEMBL screening assays

250 unique, capped per target: 250 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024907	Binding	Binding affinity to human EPHA3 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

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FD	Abcam HCT 116 EPHA3 KO	Cancer cell line	Male
CVCL_B8V9	Abcam MCF-7 EPHA3 KO	Cancer cell line	Female
CVCL_B9HL	Abcam A-549 EPHA3 KO	Cancer cell line	Male
CVCL_SM13	HAP1 EPHA3 (-) 1	Cancer cell line	Male
CVCL_SM14	HAP1 EPHA3 (-) 2	Cancer cell line	Male
CVCL_ZV65	LK63/A3KD	Cancer cell line	Sex unspecified
CVCL_ZV66	Reh/EphA3	Cancer cell line	Female

Clinical trials (associated diseases)

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