EPHA4

Summary

EPHA4 (EPH receptor A4, HGNC:3388) is a protein-coding gene on chromosome 2q36.1, encoding Ephrin type-A receptor 4 (P54764). Receptor tyrosine kinase which binds 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. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2043 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 24
• Clinical variants (ClinVar): 309 total — 2 pathogenic, 2 likely-pathogenic
• Druggable target: yes — 34 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004438

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3388
Approved symbol	EPHA4
Name	EPH receptor A4
Location	2q36.1
Locus type	gene with protein product
Status	Approved
Aliases	Hek8
Ensembl gene	ENSG00000116106
Ensembl biotype	protein_coding
OMIM	602188
Entrez	2043

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000281821, ENST00000409854, ENST00000409938, ENST00000415749, ENST00000419964, ENST00000424339, ENST00000434266, ENST00000441679, ENST00000443796, ENST00000463446, ENST00000469354, ENST00000472696, ENST00000495693, ENST00000541600, ENST00000891631

RefSeq mRNA: 4 — MANE Select: NM_004438 NM_001304536, NM_001304537, NM_001363748, NM_004438

CCDS: CCDS2447, CCDS86924

Canonical transcript exons

ENST00000281821 — 18 exons

Exon	Start	End
ENSE00001147196	221425209	221426142
ENSE00001147202	221572158	221572304
ENSE00001923673	221418027	221420552
ENSE00003673266	221568718	221568785
ENSE00003889299	221434142	221434291
ENSE00003890778	221443493	221443606
ENSE00003891664	221426464	221426619
ENSE00003892188	221429958	221430151
ENSE00003892980	221436399	221436608
ENSE00003893269	221482352	221482690
ENSE00003893342	221456613	221456772
ENSE00003893506	221446123	221446181
ENSE00003893797	221457866	221457990
ENSE00003894137	221455547	221455658
ENSE00003895124	221442829	221443014
ENSE00003896030	221563731	221564394
ENSE00003896104	221437061	221437122
ENSE00003896154	221501017	221501172

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4624 / max 1106.1025, expressed in 1290 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34118	10.3989	1290
34110	0.0635	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	97.43	gold quality
frontal pole	UBERON:0002795	96.90	gold quality
middle temporal gyrus	UBERON:0002771	96.77	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.46	gold quality
endothelial cell	CL:0000115	96.29	gold quality
primary visual cortex	UBERON:0002436	95.30	gold quality
superior frontal gyrus	UBERON:0002661	95.30	gold quality
parietal lobe	UBERON:0001872	95.23	gold quality
postcentral gyrus	UBERON:0002581	95.21	gold quality
palpebral conjunctiva	UBERON:0001812	94.87	gold quality
endometrium epithelium	UBERON:0004811	94.63	gold quality
occipital lobe	UBERON:0002021	94.23	gold quality
nipple	UBERON:0002030	93.47	gold quality
entorhinal cortex	UBERON:0002728	93.09	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.04	gold quality
ganglionic eminence	UBERON:0004023	92.86	gold quality
frontal lobe	UBERON:0016525	92.45	gold quality
frontal cortex	UBERON:0001870	92.44	gold quality
prefrontal cortex	UBERON:0000451	92.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.13	gold quality
cerebral cortex	UBERON:0000956	91.83	gold quality
neocortex	UBERON:0001950	91.81	gold quality
secondary oocyte	CL:0000655	91.10	gold quality
right frontal lobe	UBERON:0002810	90.90	gold quality
adrenal tissue	UBERON:0018303	90.84	gold quality
embryo	UBERON:0000922	90.20	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.10	gold quality
cortical plate	UBERON:0005343	90.09	gold quality
Ammon’s horn	UBERON:0001954	89.88	gold quality
eye	UBERON:0000970	89.73	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	91.19
E-HCAD-35	yes	90.01
E-HCAD-25	yes	84.67
E-ANND-3	yes	10.65
E-MTAB-6386	no	61.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2, FOXO1, HOXA13, HOXD13, MESP2, NFIA, NFIB, NFIX, PAX3, TWIST1

miRNA regulators (miRDB)

325 targeting EPHA4, 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-4262	100.00	73.26	3931
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-181A-5P	99.99	72.96	2995

Literature-anchored findings (GeneRIF, showing 40)

• Human platelets express EphA4 and EphB1, and the ligand, ephrinB1. Forced clustering of EphA4 or ephrinB1 led to cytoskeletal reorganization, adhesion to fibrinogen, and alpha-granule secretion. (PMID:12084815)
• Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca(++) and this is accomplished in part by activating Rap1 (PMID:14576067)
• The tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sezary Syndrome. (PMID:15313894)
• EphA4 is physically associated with alpha(IIb)beta(3) in resting platelets, increases its surface expression when platelets are activated, and colocalizes with alpha(IIb)beta(3) at sites of contact between platelets. (PMID:15994237)
• FGF-receptor-mediated mitogen-activated protein kinase stimulation is potentiated in cells costimulated with ephrin-A1 (PMID:16365308)
• The expression of EphA4 in astrocyte progenitor cells and in the astrocyte meshwork at the optic nerve head has implications for optic nerve pathologies. (PMID:16574431)
• Overexpression of EphA4 receptor is associated with pancreatic ductal adenocarcinoma (PMID:16965393)
• overexpression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer (PMID:18695888)
• These results indicate that EphA4 plays an important role in malignant phenotypes of glioblastoma by enhancing cell proliferation and migration through accelerating a canonical FGFR signaling pathway. (PMID:18790757)
• Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. (PMID:18837080)
• Eph-A4 expression was significantly associated with tumor proliferative capacity in pancreatic ductal adenocarcinoma. (PMID:19949912)
• The signaling complex appears to integrate the input from FGFR and EphA4, and release the output signal through FRS2alpha. (PMID:20184660)
• these results suggest that the ligand promiscuity of the Ephs is directly correlated with the structural flexibility of the ligand-binding surface of the receptor. (PMID:20678482)
• EphA4 expression maintains adult neural stem cells in an undifferentiated state. (PMID:21444754)
• The present data suggest that Eph-A2, but not Eph-A4, overexpression may be associated with the malignant transformation of thyroid neoplasia. (PMID:21873938)
• Data found significant correlations between ephA2, ephA4, ephA7, ephB4, and ephB6 and overall and/or recurrence-free survival in large microarray datasets. (PMID:21935409)
• The platelet P2Y12 receptor contributes to granule secretion through Ephrin A4 receptor. (PMID:22273509)
• The present study demonstrates that EphA4 is expressed on neurons in multiple regions of the intact human brain and is markedly upregulated on activated astrocytes after TBI (PMID:22318127)
• EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, possibly by affecting cancer cell migration and invasion. (PMID:22807579)
• Epha4 modulates the vulnerability of motor neurons to axonal degeneration and may represent a new target for therapeutic intervention in ALS. (PMID:22922411)
• High Eph A4 expression is associated with choriocarcinoma invasion. (PMID:23429488)
• Data indicate that ephrin-A5 binding directly facilitates the formation of Eph/ephrin clusters by inducing conformational changes in the ligand-binding domain (LBD) of EphA4. (PMID:23959867)
• EphA4 induced accumulation of amyloid precursor protein through a Lyn-mediated pathway. (PMID:24217950)
• EPHA4 is overexpressed but not functionally active in Sezary syndrome. (PMID:26376612)
• Host EphA4 expression regulates cancer development mainly via EphA4-mediated IGF1 synthesis signal. (PMID:26923183)
• Reduced EphA4 expression is associated with EBV-associated B lymphoma. (PMID:27338098)
• EphA4 was reduced in breast carcinoma, which is associated with high grade, advanced TNM stage, lymph node metastasis, and poor outcome of patients (PMID:27478038)
• the PI3K/AKT, Wnt/beta-catenin signaling pathways as well as ERK1/2 downstream of EPHA4 receptor activation, play an important role in the regulation of events related with the EMT development, which may be associated with the therapeutic failure in rectal cancer after radiotherapy. (PMID:27632701)
• No difference was found in the expression of EPHA4 in morphologically normal glands, HGPIN, or prostatic cancer. (PMID:27804940)
• The expression of both EphA4-FL and EphA4-N was significantly higher in the nervous tissue of SOD1(G93A) compared to wild-type mice suggesting that both forms are modulated during the disease process. (PMID:28153688)
• Findings demonstrated that mutant alpha2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant alpha2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling (PMID:28346224)
• we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion-mediated drug resistance in multiple myeloma. (PMID:28351297)
• Molecular interactions of EphA4, growth hormone receptor, Jak2, and STAT5B have been described. (PMID:28686668)
• These findings confirmed that EphA4 is a direct target gene of miR-335 and that miR-335 suppresses breast cancer cell proliferation and motility in part by directly inhibiting EphA4 expression. (PMID:28795314)
• MiR-519d down-regulates EphA4 expression in melanoma. (PMID:29093007)
• our data revealed a strong association between high EPHA4 expression and advanced tumor stage, aggressive BLBC molecular subtype and poor prognosis. Importantly, we found significant co-expression of EPHA4 and the TGFbeta receptor type-2 (TGFbetaR2) in breast cancer subtypes associated with increased tumor relapse and drug resistance. (PMID:29101386)
• These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator. (PMID:29114064)
• Therefore EphA4 is an emerging AbetaOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in Alzheimer’s disease. (PMID:29378302)
• High erythropoietin-producing hepatocellular carcinoma receptor A (EphA) 1, 2, and 4 expression levels were significantly related to recurrence. (PMID:29491103)
• blockage of EphA4/ephrin signaling between neuron and microglia decreased in oxygen-glucose deprivation and reperfusion -induced injury by promoting alternative activation of microglia via RhoA/ROCK2 signaling. (PMID:30361852)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	epha4a	ENSDARG00000054454
mus_musculus	Epha4	ENSMUSG00000026235
rattus_norvegicus	Epha4	ENSRNOG00000013213

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), 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 4 — P54764 (reviewed: P54764)

Alternative names: EPH-like kinase 8, Tyrosine-protein kinase TYRO1, Tyrosine-protein kinase receptor SEK

All UniProt accessions (8): P54764, C9JEM6, C9JFX5, C9JIX8, E9PG71, F5GZZ5, H7C1N8, H7C2W7

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which binds 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, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at ‘Tyr-15’ which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, also plays a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium. During development of the cochlear organ of Corti, regulates pillar cell separation by forming a ternary complex with ADAM10 and CADH1 which facilitates the cleavage of CADH1 by ADAM10 and disruption of adherens junctions. Phosphorylates CAPRIN1, promoting CAPRIN1-dependent formation of a membraneless compartment.

Subunit / interactions. Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (phosphorylated at position Tyr-602) with FYN. Interacts with CDK5, CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation. Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions.

Subcellular location. Cell membrane. Cell projection. Axon. Dendrite. Postsynaptic density membrane. Early endosome. Cell junction. Adherens junction.

Tissue specificity. Ubiquitous.

Domain organisation. The protein kinase domain mediates interaction with NGEF.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P54764-1	1	yes
P54764-2	2

RefSeq proteins (4): NP_001291465, NP_001291466, NP_001350677, NP_004429* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001090	EPH_LBD	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001426	Tyr_kinase_rcpt_V_CS	Conserved_site
IPR001660	SAM	Domain
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
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
IPR030602	EphA4_SAM	Domain
IPR034270	EphA4_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF01404, PF07647, 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 (80 total): strand 40, domain 5, modified residue 4, glycosylation site 4, sequence variant 4, sequence conflict 4, helix 4, turn 3, binding site 2, topological domain 2, mutagenesis site 2, signal peptide 1, chain 1, short sequence motif 1, active site 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
7OFV	X-RAY DIFFRACTION	1.43
5JR2	X-RAY DIFFRACTION	1.75
2WO1	X-RAY DIFFRACTION	1.85
4M4P	X-RAY DIFFRACTION	2.08
2WO3	X-RAY DIFFRACTION	2.35
4W4Z	X-RAY DIFFRACTION	2.41
4W50	X-RAY DIFFRACTION	2.42
2WO2	X-RAY DIFFRACTION	2.45
3GXU	X-RAY DIFFRACTION	2.5
9CY8	X-RAY DIFFRACTION	2.5
3CKH	X-RAY DIFFRACTION	2.8
4M4R	X-RAY DIFFRACTION	3.13
4BK4	X-RAY DIFFRACTION	3.65
4BK5	X-RAY DIFFRACTION	4
4BKF	X-RAY DIFFRACTION	4.65
4BKA	X-RAY DIFFRACTION	5.3
2LW8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54764-F1	83.93	0.55

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 (2): 627–635; 653

Post-translational modifications (4): 596, 602, 779, 928

Glycosylation sites (4): 235, 340, 408, 545

Mutagenesis-validated functional residues (2):

Position	Phenotype
40	10-fold reduced affinity for efnb2; when associated with a-42.
42	10-fold reduced affinity for efnb2; when associated with a-40.

Function

Pathways and Gene Ontology

Reactome pathways

4 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
R-HSA-9824272	Somitogenesis

MSigDB gene sets: 587 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, TGCACTT_MIR519C_MIR519B_MIR519A, PEREZ_TP63_TARGETS

GO Biological Process (50): cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), axon guidance (GO:0007411), adult walking behavior (GO:0007628), motor neuron axon guidance (GO:0008045), positive regulation of cell population proliferation (GO:0008284), glial cell migration (GO:0008347), negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of neuron projection development (GO:0010977), negative regulation of translation (GO:0017148), corticospinal tract morphogenesis (GO:0021957), positive regulation of cell migration (GO:0030335), negative regulation of cell migration (GO:0030336), adherens junction organization (GO:0034332), regulation of GTPase activity (GO:0043087), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of cell adhesion (GO:0045785), positive regulation of JNK cascade (GO:0046330), ephrin receptor signaling pathway (GO:0048013), negative regulation of axon regeneration (GO:0048681), regulation of astrocyte differentiation (GO:0048710), regulation of axonogenesis (GO:0050770), positive regulation of dendrite morphogenesis (GO:0050775), protein stabilization (GO:0050821), innervation (GO:0060384), regulation of dendritic spine morphogenesis (GO:0061001), negative regulation of ERK1 and ERK2 cascade (GO:0070373), nephric duct morphogenesis (GO:0072178), cochlea development (GO:0090102), fasciculation of sensory neuron axon (GO:0097155), fasciculation of motor neuron axon (GO:0097156), neuron projection guidance (GO:0097485), synapse pruning (GO:0098883), neuron projection fasciculation (GO:0106030), negative regulation of cellular response to hypoxia (GO:1900038), negative regulation of long-term synaptic potentiation (GO:1900272), positive regulation of amyloid-beta formation (GO:1902004), positive regulation of intracellular signal transduction (GO:1902533), positive regulation of amyloid precursor protein catabolic process (GO:1902993), obsolete negative regulation of proteolysis involved in protein catabolic process (GO:1903051)

GO Molecular Function (17): amyloid-beta binding (GO:0001540), protein tyrosine kinase activity (GO:0004713), ephrin receptor activity (GO:0005003), GPI-linked ephrin receptor activity (GO:0005004), transmembrane-ephrin receptor activity (GO:0005005), ATP binding (GO:0005524), kinase activity (GO:0016301), PH domain binding (GO:0042731), identical protein binding (GO:0042802), ephrin receptor binding (GO:0046875), DH domain binding (GO:0097161), protein tyrosine kinase binding (GO:1990782), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transmembrane receptor protein tyrosine kinase activity (GO:0004714), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (28): cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), plasma membrane (GO:0005886), adherens junction (GO:0005912), cell surface (GO:0009986), filopodium (GO:0030175), axon (GO:0030424), dendrite (GO:0030425), neuromuscular junction (GO:0031594), early endosome membrane (GO:0031901), presynaptic membrane (GO:0042734), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), perikaryon (GO:0043204), axon terminus (GO:0043679), axonal growth cone (GO:0044295), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), endosome (GO:0005768), early endosome (GO:0005769), postsynaptic density (GO:0014069), membrane (GO:0016020), cell projection (GO:0042995), cell body (GO:0044297), synapse (GO:0045202), postsynaptic membrane (GO:0045211), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
EPH-Ephrin signaling	2
Axon guidance	1
Formation of paraxial mesoderm	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell migration	3
synapse	3
cell adhesion	2
regulation of cell adhesion	2
positive regulation of cellular process	2
regulation of cell migration	2
ephrin receptor activity	2
protein domain specific binding	2
neuron projection	2
presynapse	2
dendrite	2
cellular process	1
negative regulation of cellular process	1
axonogenesis	1
neuron projection guidance	1
adult locomotory behavior	1
walking behavior	1
axon guidance	1
cell population proliferation	1
regulation of cell population proliferation	1
gliogenesis	1
epithelial to mesenchymal transition	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
negative regulation of cell projection organization	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
central nervous system projection neuron axonogenesis	1
positive regulation of cell motility	1
negative regulation of cell motility	1
cell-cell junction organization	1
GTPase activity	1
regulation of hydrolase activity	1
negative regulation of apoptotic process	1

Protein interactions and networks

STRING

2850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHA4	EFNA1	P20827	999
EPHA4	EFNA3	P52797	999
EPHA4	EFNA4	P52798	999
EPHA4	EFNA2	O43921	998
EPHA4	EFNB3	Q15768	998
EPHA4	EFNB2	P52799	998
EPHA4	EFNA5	P52803	998
EPHA4	EFNB1	P98172	997
EPHA4	THY1	P04216	895
EPHA4	LAD1	O00515	806
EPHA4	EPHB2	P29323	792
EPHA4	NGEF	Q8N5V2	786
EPHA4	ARHGEF15	O94989	783
EPHA4	NCK2	O43639	763
EPHA4	CHN1	P15882	740

IntAct

118 interactions, top by confidence:

A	B	Type	Score
EPHA4	EFNA5	psi-mi:“MI:0407”(direct interaction)	0.790
EFNA5	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.790
EPHA4	EFNB2	psi-mi:“MI:0915”(physical association)	0.780
EPHA4	EFNB2	psi-mi:“MI:0407”(direct interaction)	0.780
EPHA4	EFNB3	psi-mi:“MI:0407”(direct interaction)	0.780
EFNB2	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.780
EFNB3	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.780
GBP5	GBP1	psi-mi:“MI:0914”(association)	0.720
EPHA4	EFNA4	psi-mi:“MI:0407”(direct interaction)	0.710
EFNA4	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.710
EPHA4	EFNA2	psi-mi:“MI:0407”(direct interaction)	0.650
EPHA4	EFNA2	psi-mi:“MI:0915”(physical association)	0.650
EFNB3	DENND11	psi-mi:“MI:0914”(association)	0.640
TUBB	PLD2	psi-mi:“MI:0914”(association)	0.640
EPHA4	EFNA1	psi-mi:“MI:0407”(direct interaction)	0.620
EFNA1	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.620
EFNB1	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.600
EPHA4	EFNB1	psi-mi:“MI:0403”(colocalization)	0.600
EPHA4	FABP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (246): EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), FGFR1 (Affinity Capture-Western), EPHA4 (Affinity Capture-Western), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS)

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

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
EPHA4	“up-regulates activity”	STAT5B	phosphorylation
EPHA4	“up-regulates activity”	JAK2	phosphorylation
EPHA4	“up-regulates activity”	GHR	phosphorylation
EPHA4	“up-regulates activity”	FGFR1	phosphorylation
EFNA1	up-regulates	EPHA4	binding
EFNA2	up-regulates	EPHA4	binding
EFNA3	up-regulates	EPHA4	binding
EFNA5	up-regulates	EPHA4	binding
EFNB3	up-regulates	EPHA4	binding
NFIA	“up-regulates quantity”	EPHA4	“transcriptional regulation”
NFIB	“up-regulates quantity”	EPHA4	“transcriptional regulation”
NFIX	“up-regulates quantity”	EPHA4	“transcriptional regulation”
EPHA4	“up-regulates activity”	EPHA4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
EPH-ephrin mediated repulsion of cells	9	23.8×	8e-08
EPHA-mediated growth cone collapse	5	22.9×	6e-04
EPH-Ephrin signaling	9	17.9×	6e-07
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	11.7×	4e-03
The role of GTSE1 in G2/M progression after G2 checkpoint	6	11.6×	2e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	11.2×	2e-03
COPI-dependent Golgi-to-ER retrograde traffic	6	8.0×	6e-03
COPI-mediated anterograde transport	6	7.9×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	9	29.8×	1e-08
axon guidance	11	9.6×	9e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	162
Likely benign	104
Benign	22

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
59166	GRCh38/hg38 2q36.1(chr2:220837832-221627616)x3	Pathogenic
995917	GRCh37/hg19 2q36.1(chr2:222199886-222298997)	Pathogenic
2502421	NM_004438.5(EPHA4):c.1655_1656del (p.Ser552fs)	Likely pathogenic
431727	NM_004438.5(EPHA4):c.2242G>A (p.Ala748Thr)	Likely pathogenic

SpliceAI

3201 predictions. Top by Δscore:

Variant	Effect	Δscore
2:221426455:AGTAC:A	donor_loss	1.0000
2:221426460:TTACT:T	donor_loss	1.0000
2:221426461:T:TC	donor_loss	1.0000
2:221426462:A:AC	donor_gain	1.0000
2:221426462:ACT:A	donor_gain	1.0000
2:221426462:ACTC:A	donor_gain	1.0000
2:221426463:C:CT	donor_gain	1.0000
2:221426463:CT:C	donor_gain	1.0000
2:221426463:CTC:C	donor_gain	1.0000
2:221426463:CTCC:C	donor_gain	1.0000
2:221426463:CTCCT:C	donor_gain	1.0000
2:221426615:TAGGT:T	acceptor_gain	1.0000
2:221426616:AGGT:A	acceptor_gain	1.0000
2:221426617:GGT:G	acceptor_gain	1.0000
2:221426618:GT:G	acceptor_gain	1.0000
2:221426618:GTCTA:G	acceptor_loss	1.0000
2:221426620:C:CC	acceptor_gain	1.0000
2:221426620:CTAG:C	acceptor_loss	1.0000
2:221426621:T:A	acceptor_loss	1.0000
2:221429954:TGACC:T	donor_loss	1.0000
2:221429955:GACC:G	donor_loss	1.0000
2:221429957:C:A	donor_loss	1.0000
2:221430151:CC:C	acceptor_loss	1.0000
2:221430152:C:CA	acceptor_loss	1.0000
2:221430153:T:C	acceptor_loss	1.0000
2:221434140:A:AC	donor_gain	1.0000
2:221434140:ACAT:A	donor_gain	1.0000
2:221434141:C:CC	donor_gain	1.0000
2:221434141:CA:C	donor_gain	1.0000
2:221434141:CAT:C	donor_gain	1.0000

AlphaMissense

6509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:221430044:C:A	R868S	1.000
2:221430044:C:G	R868S	1.000
2:221430045:C:A	R868M	1.000
2:221430045:C:G	R868T	1.000
2:221430067:A:G	W861R	1.000
2:221430067:A:T	W861R	1.000
2:221430068:G:C	C860W	1.000
2:221430081:A:G	L856P	1.000
2:221430120:A:G	L843S	1.000
2:221434167:G:T	P824H	1.000
2:221434177:C:A	G821W	1.000
2:221434193:C:A	W815C	1.000
2:221434193:C:G	W815C	1.000
2:221434195:A:G	W815R	1.000
2:221434195:A:T	W815R	1.000
2:221434206:C:T	G811E	1.000
2:221434207:C:G	G811R	1.000
2:221434207:C:T	G811R	1.000
2:221434211:G:C	S809R	1.000
2:221434211:G:T	S809R	1.000
2:221434213:T:G	S809R	1.000
2:221434214:C:A	W808C	1.000
2:221434214:C:G	W808C	1.000
2:221434216:A:G	W808R	1.000
2:221434216:A:T	W808R	1.000
2:221434222:C:G	D806H	1.000
2:221434223:A:C	S805R	1.000
2:221434223:A:T	S805R	1.000
2:221434225:T:G	S805R	1.000
2:221434235:G:C	F801L	1.000

dbSNP variants (sampled 300 via entrez): RS1000017932 (2:221504207 C>G), RS1000034656 (2:221438568 A>C,G), RS1000044529 (2:221497524 A>G), RS1000053768 (2:221573158 C>A,G,T), RS1000086353 (2:221447461 C>T), RS1000095575 (2:221529186 GA>G,GAA), RS1000108759 (2:221570754 G>A), RS1000126246 (2:221521680 A>G), RS1000149518 (2:221528939 G>A,T), RS1000162260 (2:221444193 G>C), RS1000246482 (2:221432990 A>G), RS1000246844 (2:221474191 A>C,G), RS1000308845 (2:221491377 T>C), RS1000331161 (2:221485535 C>A,T), RS1000333283 (2:221564583 T>TG)

Disease associations

OMIM: gene MIM:602188 | disease phenotypes: MIM:193500

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (2): Waardenburg syndrome type 1 (MONDO:0008670), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Waardenburg syndrome type 1 (Orphanet:894)

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000573_1	Brain imaging	1.000000e-07
GCST002074_1	Paclitaxel-induced neuropathy	1.000000e-06
GCST002441_10	Immune response to measles-mumps-rubella vaccine	2.000000e-07
GCST002830_2	Urate levels in lean individuals	4.000000e-06
GCST002875_31	Diisocyanate-induced asthma	5.000000e-06
GCST003128_3	Adolescent idiopathic scoliosis	8.000000e-13
GCST003999_22	Nose size	3.000000e-07
GCST006075_3	Hair color	1.000000e-100
GCST006979_91	Heel bone mineral density	6.000000e-14
GCST006988_207	Blond vs. brown/black hair color	1.000000e-64
GCST006988_208	Blond vs. brown/black hair color	2.000000e-86
GCST006988_41	Blond vs. brown/black hair color	3.000000e-13
GCST006988_44	Blond vs. brown/black hair color	1.000000e-24
GCST006989_23	Brown vs. black hair color	2.000000e-22
GCST006989_24	Brown vs. black hair color	2.000000e-14
GCST007637_31	Diffusing capacity of carbon monoxide	5.000000e-06
GCST009177_2	Entorhinal cortical volume	5.000000e-06
GCST009221_5	Rostral anterior cingulate cortex volume	9.000000e-06
GCST009309_2	Face memory	3.000000e-06
GCST010698_28	Subcortical volume (min-P)	3.000000e-08
GCST010699_51	Brain morphology (min-P)	3.000000e-08
GCST010701_96	Cortical surface area (MOSTest)	9.000000e-13
GCST010702_107	Subcortical volume (MOSTest)	1.000000e-09
GCST010703_67	Brain morphology (MOSTest)	2.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004645	response to vaccine
EFO:0004531	urate measurement
EFO:0006995	response to diisocyanate
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0005092	entorhinal cortical volume
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL3988 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

34 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 292,350 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL5416410	DASATINIB	4	655
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3544983	TESEVATINIB	3	2,819
CHEMBL3545154	POZIOTINIB	3	1,560
CHEMBL483158	ALISERTIB	3	2,305
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL119385	NEFLAMAPIMOD	2	1,603
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL206834	BAFETINIB	2	1,024
CHEMBL2408045	SAPITINIB	2
CHEMBL3039525	GOLVATINIB	2
CHEMBL402548	DANUSERTIB	2
CHEMBL403989	TG100-801	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL558752	RAF-265	2
CHEMBL564829	MILCICLIB	2
CHEMBL572878	TOZASERTIB	2
CHEMBL259084	MLN-8054	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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 66 [PMID: 19788238]	Inhibition	8.48	pIC50
compound 20 [PMID: 23489211]	Inhibition	5.57	pIC50

Binding affinities (BindingDB)

21 measured of 26 human assays (26 total across all organisms); most potent 21 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
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
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
123C4	KI	640 nM
120H10	KI	960 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
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
123C2	KI	1590 nM
123C7	KI	1590 nM
CI-1033	KD	1700 nM
EphA4-LBC inhibitor, Compound 22	KI	2140 nM
123C3	KI	2220 nM
123C5	KI	2570 nM
123B1	KI	3040 nM
123C6	KI	3140 nM
123C12	KI	7670 nM
120G1	KI	14000 nM
120G2	KI	100000 nM

ChEMBL bioactivities

176 potent at pChembl≥5 of 180 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	Kd	1.2	nM	DASATINIB
8.72	Kd	1.9	nM	FORETINIB
8.70	Kd	2	nM	CHEMBL400402
8.48	IC50	3.3	nM	CHEMBL566515
8.39	IC50	4.1	nM	DASATINIB ANHYDROUS
8.30	Kd	5	nM	CHEMBL249097
8.15	Kd	7	nM	DASATINIB
8.14	Kd	7.3	nM	DASATINIB ANHYDROUS
8.14	Kd	7.311	nM	DASATINIB ANHYDROUS
8.12	IC50	7.6	nM	CHEMBL3752910
8.08	Kd	8.3	nM	CHEMBL386051
8.07	IC50	8.5	nM	STAUROSPORINE
8.05	IC50	9	nM	CHEMBL3787112
8.00	IC50	10	nM	STAUROSPORINE
7.92	IC50	12	nM	CHEMBL4462106
7.92	IC50	12	nM	CHEMBL4530593
7.90	IC50	12.5	nM	STAUROSPORINE
7.77	IC50	17	nM	CHEMBL4464968
7.75	Kd	18	nM	BOSUTINIB
7.72	Kd	19	nM	CHEMBL4530593
7.66	Kd	22	nM	TAK-901
7.66	IC50	22	nM	CHEMBL4464855
7.60	IC50	25	nM	CHEMBL4440005
7.57	IC50	27	nM	CHEMBL4436732
7.57	Kd	27	nM	CHEMBL4464968
7.52	Kd	30	nM	CHEMBL4436732
7.47	IC50	34	nM	CHEMBL4458170
7.43	EC50	37	nM	CHEMBL5566108
7.43	EC50	37	nM	CHEMBL5574808
7.42	IC50	38	nM	CHEMBL4447628
7.40	IC50	40	nM	CHEMBL4539149
7.39	IC50	41	nM	CHEMBL4516686
7.35	Kd	45	nM	CHEMBL4449863
7.32	EC50	48	nM	CHEMBL1198514
7.30	IC50	50	nM	CHEMBL4449863
7.27	IC50	54	nM	CHEMBL4434643
7.24	EC50	57	nM	CHEMBL5568747
7.23	Kd	59	nM	BOSUTINIB
7.22	Kd	60	nM	CHEMBL4878061
7.22	EC50	60	nM	CHEMBL5566270
7.16	IC50	70	nM	DORAMAPIMOD
7.13	IC50	74	nM	CHEMBL4216073
7.11	Kd	77	nM	CHEMBL4853905
7.08	IC50	83	nM	CHEMBL4436577
7.08	EC50	84	nM	CHEMBL5572722
7.03	Kd	94	nM	CHEMBL4846015
6.97	Kd	106	nM	CHEMBL4872754
6.97	Kd	106	nM	CHEMBL4879331
6.95	Kd	113	nM	CHEMBL4865183
6.88	Kd	132	nM	CHEMBL4848686

PubChem BioAssay actives

180 with measured affinity, of 1261 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	435795: Binding constant for EPHA4 kinase domain	kd	0.0012	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	624952: Binding constant for EPHA4 kinase domain	kd	0.0019	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1424989: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0020	uM
7-(5-hydroxy-2-methylphenyl)-6-(2-methoxyphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione	441388: Inhibition of EphA4 by [gamma33-P]ATP based assay	ic50	0.0033	uM
Dasatinib	2147742: Inhibition of Nano Luc-fused full length C-terminal EPHA4 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0041	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389073: Binding affinity to human EPHA4	kd	0.0050	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147742: Inhibition of Nano Luc-fused full length C-terminal EPHA4 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0076	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624952: Binding constant for EPHA4 kinase domain	kd	0.0083	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	1715366: Inhibition of human EPHA4 using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.0085	uM
3-[4-amino-7-[3-(azetidin-1-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-5-yl]phenol	1291006: Inhibition of EphA4 (unknown origin) in presence of [gamma33P]ATP	ic50	0.0090	uM
3-[(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-20-(3-carbamimidamidopropyl)-4-carbamoyl-7-(2-carboxyethyl)-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-octazacyclotriacont-13-yl]propanoic acid	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0120	uM
3-[(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-1-(3-aminopropanoyl)pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-20-(3-carbamimidamidopropyl)-4-carbamoyl-7-(2-carboxyethyl)-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-octazacyclotriacont-13-yl]propanoic acid	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0120	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0170	uM
Bosutinib	624952: Binding constant for EPHA4 kinase domain	kd	0.0180	uM
3-[(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-20-(3-carbamimidamidopropyl)-4-carbamoyl-13-(carboxymethyl)-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-octazacyclotriacont-7-yl]propanoic acid	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0220	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1424989: 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	0.0220	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-(3-aminopropanoylamino)-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0250	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-1-[(2S)-2-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0270	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-(4-aminobutanoylamino)-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0340	uM
6-(4-fluoro-3-methoxyphenyl)-15-methoxy-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0370	uM
6-(4-chloro-2-fluoro-5-methoxyphenyl)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0370	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-20-[3-(diaminomethylideneamino)propyl]-7,13-bis(hydroxymethyl)-23-[(4-hydroxyphenyl)methyl]-29-[[(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-pyrrolidine-2-carbonyl]amino]propanoyl]amino]-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0380	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-20-[3-(diaminomethylideneamino)propyl]-7,13-bis(hydroxymethyl)-23-[(4-hydroxyphenyl)methyl]-29-[[(2S)-3-(4-hydroxyphenyl)-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0400	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[(2-aminoacetyl)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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0410	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-[[(2S)-1-[(2R)-2-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	1632975: Binding affinity to 6His-tagged EphA4 C204A mutant (29 to 104 residues) (unknown origin) expressed in Escherichia coli Origami 2 (DE3) by isothermal titration calorimetry	kd	0.0450	uM
N-(2-chlorophenyl)-6-piperidin-4-ylimidazo[1,2-a]pyridine-3-carboxamide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0480	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-(5-aminopentanoylamino)-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0540	uM
6-(4-bromo-3-methoxyphenyl)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0570	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	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.0600	uM
6-(4-fluoro-3-methoxyphenyl)-15-(2-methoxyethoxy)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0600	uM
4-amino-N-[(2S)-1-[[(2S)-3-(4-chlorophenyl)-1-[[(2S)-1-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-1-oxo-3-pyridin-4-ylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(5-hydroxy-1H-indol-3-yl)-1-oxopropan-2-yl]butanamide	1802656: Isothermal Titration Calorimetry (ITC) from Article 10.1016/j.chembiol.2017.01.006: “Potent and Selective EphA4 Agonists for the Treatment of ALS.”	kd	0.0620	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	636424: Inhibition of EPHA4	ic50	0.0700	uM
N-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	1367767: Inhibition of EphA4 (unknown origin)	ic50	0.0740	uM
trans-(1S,3S)-3-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-6-(diaminomethylideneamino)-1-[[2-[4-(morpholin-4-ylmethyl)anilino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-[4-(2-methoxyphenyl)phenyl]-1-oxopropan-2-yl]amino]-3-(5-hydroxy-1H-indol-3-yl)-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.0770	uM
(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-(6-aminohexanoylamino)-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	1632973: Antagonist activity against human EphA4 receptor assessed as inhibition of binding of alkaline phosphatase-fused ephrin-A5 to immobilized EphA4 Fc by ELISA	ic50	0.0830	uM
6-(3,4-dichlorophenyl)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.0840	uM
(2S)-2-[[(2S)-2-[[(2S)-2-(4-aminobutanoylamino)-3-(5-hydroxy-1H-indol-3-yl)propanoyl]amino]-3-(4-phenylphenyl)propanoyl]amino]-6-(diaminomethylideneamino)-N-[2-(4-morpholin-4-ylanilino)-2-oxoethyl]hexanamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.0940	uM
trans-(1S,3S)-3-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-6-(diaminomethylideneamino)-1-[[2-(4-morpholin-4-ylanilino)-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-[4-(2-methoxyphenyl)phenyl]-1-oxopropan-2-yl]amino]-3-(5-hydroxy-1H-indol-3-yl)-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1060	uM
(2S)-2-[[(2S)-2-[[(2S)-2-(4-aminobutanoylamino)-3-(5-hydroxy-1H-indol-3-yl)propanoyl]amino]-3-(4-phenylphenyl)propanoyl]amino]-6-(diaminomethylideneamino)-N-[2-[4-(morpholin-4-ylmethyl)anilino]-2-oxoethyl]hexanamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1060	uM
trans-(1S,3S)-3-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-6-(diaminomethylideneamino)-1-[[2-(4-morpholin-4-ylanilino)-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-(4-phenylphenyl)propan-2-yl]amino]-3-(5-hydroxy-1H-indol-3-yl)-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1130	uM
(2S)-2-[[(2S)-2-[[(2S)-2-(4-aminobutanoylamino)-3-(5-hydroxy-1H-indol-3-yl)propanoyl]amino]-3-(4-phenylphenyl)propanoyl]amino]-N-(2-anilino-2-oxoethyl)-6-(diaminomethylideneamino)hexanamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1320	uM
trans-(1S,3S)-3-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-6-(diaminomethylideneamino)-1-[[2-[4-(morpholin-4-ylmethyl)anilino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-(4-phenylphenyl)propan-2-yl]amino]-3-(5-hydroxy-1H-indol-3-yl)-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1440	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	624952: Binding constant for EPHA4 kinase domain	kd	0.1500	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	1424989: 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	0.1590	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	1424989: 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
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1424989: 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	0.1810	uM
6-(2,4-difluoro-3-methoxyphenyl)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110401: Inhibition of full length EPHA4 (unknown origin) expressed in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of K4 tracer by NanoBRET assay	ec50	0.1900	uM
(2S)-2-[[(2S)-2-[[(2S)-2-(4-aminobutanoylamino)-3-(5-hydroxy-1H-indol-3-yl)propanoyl]amino]-3-(4-phenylphenyl)propanoyl]amino]-6-(diaminomethylideneamino)-N-[2-(2-hydroxyanilino)-2-oxoethyl]hexanamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1910	uM
(2S)-2-[[(2S)-2-[[(2S)-2-(4-aminobutanoylamino)-3-(5-hydroxy-1H-indol-3-yl)propanoyl]amino]-3-[4-(2-methoxyphenyl)phenyl]propanoyl]amino]-6-(diaminomethylideneamino)hexanamide	1765936: Binding affinity to N-terminal His tagged EphA4 LBD (unknown origin) (29 to 209 residues) expressed in Rosetta-Gami B(DE3) cells by isothermal titration calorimetry	kd	0.1960	uM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	1734784: Inhibition of human recombinant EPHA4 (601 to 892 residues) using poly(Glu,Tyr)4:1 as substrate incubated for 40 mins in presence of [gamma33P-ATP] by radiometric scintillation counting analysis	ic50	0.2270	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects cotreatment, decreases expression, affects expression	8
sodium arsenite	affects cotreatment, increases abundance, affects methylation, decreases expression	4
Estradiol	affects expression, increases expression, decreases expression, decreases reaction	4
trichostatin A	increases expression, affects cotreatment, decreases expression	3
Arsenic	decreases expression, increases abundance, affects cotreatment	3
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	2
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Fulvestrant	affects cotreatment, increases methylation, increases expression	2
Vorinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
kojic acid	increases expression	1
terbufos	increases methylation	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ferrous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
avobenzone	decreases expression	1

ChEMBL screening assays

286 unique, capped per target: 286 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024909	Binding	Binding affinity to human EPHA4 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RD	Abcam HeLa EPHA4 KO	Cancer cell line	Female
CVCL_SM15	HAP1 EPHA4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns