MAP2K4

Summary

MAP2K4 (mitogen-activated protein kinase kinase 4, HGNC:6844) is a protein-coding gene on chromosome 17p12, encoding Dual specificity mitogen-activated protein kinase kinase 4 (P45985). Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6416 — RefSeq curated summary.

At a glance

• GWAS associations: 104
• Clinical variants (ClinVar): 61 total
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 8 cancer types
• MANE Select transcript: NM_003010

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6844
Approved symbol	MAP2K4
Name	mitogen-activated protein kinase kinase 4
Location	17p12
Locus type	gene with protein product
Status	Approved
Aliases	MEK4, JNKK1, PRKMK4, MKK4, MAPKK4, SAPKK1, SKK1, JNKK, SEK1
Ensembl gene	ENSG00000065559
Ensembl biotype	protein_coding
OMIM	601335
Entrez	6416

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding, 7 nonsense_mediated_decay, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000353533, ENST00000415385, ENST00000536413, ENST00000538465, ENST00000579089, ENST00000581941, ENST00000582183, ENST00000582377, ENST00000582897, ENST00000585076, ENST00000602305, ENST00000602375, ENST00000602537, ENST00000602686, ENST00000602811, ENST00000905330, ENST00000905331, ENST00000905332, ENST00000905333, ENST00000905334, ENST00000937443, ENST00000937444

RefSeq mRNA: 2 — MANE Select: NM_003010 NM_001281435, NM_003010

CCDS: CCDS11162, CCDS62095

Canonical transcript exons

ENST00000353533 — 11 exons

Exon	Start	End
ENSE00001385129	12020877	12021001
ENSE00002732704	12141147	12143828
ENSE00003489631	12129139	12129287
ENSE00003524523	12125294	12125371
ENSE00003555844	12081356	12081530
ENSE00003644508	12054889	12054991
ENSE00003661925	12139839	12139884
ENSE00003705689	12110375	12110426
ENSE00003706230	12107790	12107909
ENSE00003710291	12095575	12095694
ENSE00003710941	12113233	12113360

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.9973 / max 559.7910, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159609	35.0027	1816
159611	1.3736	92
159608	1.0861	685
159610	0.5349	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	96.66	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.49	gold quality
postcentral gyrus	UBERON:0002581	95.39	gold quality
orbitofrontal cortex	UBERON:0004167	95.38	gold quality
substantia nigra pars compacta	UBERON:0001965	95.36	gold quality
middle temporal gyrus	UBERON:0002771	95.35	gold quality
superior frontal gyrus	UBERON:0002661	95.19	gold quality
prefrontal cortex	UBERON:0000451	94.98	gold quality
parietal lobe	UBERON:0001872	94.74	gold quality
calcaneal tendon	UBERON:0003701	94.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.34	gold quality
pons	UBERON:0000988	94.06	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.03	gold quality
frontal cortex	UBERON:0001870	94.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.82	gold quality
adrenal tissue	UBERON:0018303	93.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.64	gold quality
neocortex	UBERON:0001950	93.38	gold quality
cerebral cortex	UBERON:0000956	93.15	gold quality
Brodmann (1909) area 10	UBERON:0013541	92.70	gold quality
Ammon’s horn	UBERON:0001954	92.15	gold quality
cingulate cortex	UBERON:0003027	91.98	gold quality
primary visual cortex	UBERON:0002436	91.93	gold quality
right frontal lobe	UBERON:0002810	91.91	gold quality
anterior cingulate cortex	UBERON:0009835	91.90	gold quality
entorhinal cortex	UBERON:0002728	91.89	gold quality
occipital lobe	UBERON:0002021	91.81	gold quality
frontal pole	UBERON:0002795	91.69	gold quality
superior vestibular nucleus	UBERON:0007227	91.56	gold quality
telencephalon	UBERON:0001893	91.41	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	144.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HSF2, NR2C2, PITX2, TCF3

miRNA regulators (miRDB)

187 targeting MAP2K4, 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-3646	100.00	73.56	5283
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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-520D-5P	99.98	73.34	4883

Literature-anchored findings (GeneRIF, showing 40)

• There appears to be consistent rate of genetic inactivation of MAP2K4 among most tumor types, including breast cancer. (PMID:11754110)
• JNK-dependent phosphorylation and thus inactivation of Mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage (PMID:12223490)
• Jun N-terminal kinase has a role in IL-4 induction (PMID:12368275)
• Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways (PMID:12456688)
• in the setting of wild-type PTEN, PI3K- and MKK4/JNK-dependent pathways cooperate to maintain cell survival. (PMID:12714585)
• regulation of fibroblast functions important for wound healing by basal JNK activity (PMID:12730213)
• docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates (PMID:12788955)
• JNK, MKK-4, and MKK-7 form an active signaling complex in rheumatoid arthritis and this novel JNK signalsome is activated in response to IL-1 and migrates to the nucleus (PMID:13130464)
• JNK and p38 MAPK activities in UVA-induced signaling pathways leading to AP-1 activation and c-Fos expression (PMID:14511403)
• MMP-9 inhibition activity of resveratrol and its inhibition of JNK and PKC-delta may have a therapeutic potential in cancer. (PMID:14661062)
• Apoptosis signaling triggered by ascididemin is routed via CASP2 and JNKK to mitochondria. (PMID:14716300)
• Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. (PMID:15256484)
• AP-1 and JNK have roles in reactive oxygen species activation in tobacco-induced mucin production in lung cells (PMID:15262961)
• PP5 plays an important role in the survival of cells in a low oxygen environment by suppressing a hypoxia-induced ASK-1/MKK4/JNK signaling cascade that promotes an apoptotic response (PMID:15328343)
• CYLD has a role in megative regulation of JNK signaling (PMID:15496400)
• Our investigations revealed significantly reduced mRNA expression of metastases suppressor gene Mkk4 in breast cancer brain metastasis. (PMID:15592684)
• Loss of Mkk4 protein expression is associated with pancreatic carcinoma progression (PMID:15623633)
• Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis. (PMID:15670787)
• Pharmacological inhibition of oxidative stress diminished the elevated p38, JNK activity and PARP cleavage, and enhanced PD cybrid viability. (PMID:15737736)
• JIP1 and JIP3, have a cross-talk that leads to the regulation of the ASK1-SEK1-JNK signal during glucose deprivation; cross-talk between JIP3 and JIP1 is mediated through SEK1-JNK2 and Akt1. (PMID:15911620)
• Our results demonstrate that radioresistance of Saos2 osteosarcoma cells is due to NFkappaB-mediated inhibition of JNK (PMID:16167336)
• an independent role for p38 MAPK and JNK in LPA-induced IL-8 expression and secretion via NF-kappaB and AP-1 transcription respectively in human bronchial epithelial cells. (PMID:16197369)
• These results indicate that SPC stimulates the proliferation of hADSCs through the Gi/Go-PLC-JNK pathway and that LPA receptors may be responsible in part for the SPC-induced proliferation (PMID:16339111)
• The present study demonstrates that HSP cells compared to controls are more sensitive to DNA damages induced by H2O2 treatment, and that JNK phosphorylation levels are increased in HSP fibroblasts after hydrogen peroxide and serum stimuli. (PMID:16388335)
• Homozygous deletion or reduced expression of MKK4 may contribute to the development of ovarian serous carcinoma. (PMID:16627982)
• Bax is phosphorylated by stress-activated JNK and/or p38 kinase and phosphorylation of Bax leads to mitochondrial translocation prior to apoptosis (PMID:16709574)
• JNK (c-Jun N-terminal kinase) function might be modulated by targeting MKK-7 to suppress cytokine-mediated fibroblast-like synoviocytes (FLS) activation while leaving other stress responses intact. (PMID:16802349)
• p38 MAPK and JNK pathways play an important role in VEGF secretion from malignant glioma cells under normoxic conditions. (PMID:16964394)
• Phosphorylated forms of MKK4, JNK, and c-Jun were detected in salivary infiltrating mononuclear cells in Sjogren’s syndrome patients (PMID:17009014)
• MKK4 decreases phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and promotes survival in non-small-cell lung cancer (NSCLC) cells. (PMID:17158870)
• LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JN kinase. (PMID:17178861)
• The results suggest that JNK regulates human iNOS expression by stabilizing iNOS mRNA possibly by a tristetraprolin -dependent mechanism. (PMID:17322004)
• TNF-induced TRAF2-RIP1-AIP1-ASK1 complex formation and for the activation of ASK1-JNK/p38 apoptotic signaling. (PMID:17389591)
• PF4-stimulated immediate monocyte functions (oxygen radical formation) are regulated by p38 MAPK, Syk, and PI3K, whereas delayed functions (survival and cytokine expression) are controlled by Erk and JNK. (PMID:17675521)
• Cytosolic mRNA is shifted toward active polysomes in prostate tumor cells with higher levels of MKK4 protein, suggesting that MKK4 mRNA is translated more efficiently in these cells. (PMID:18337456)
• JNK3 recruits MKK4 to the beta-arrestin-2 scaffold complex by binding to the MAPK docking domain (D-domain) located within the N terminus of MKK4. (PMID:18408005)
• Disruption of signaling through MKK4 yields differential response in hypoxic colon cancer cells treated with oxaliplatin. (PMID:18436711)
• JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. (PMID:18713996)
• the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2 (PMID:19001375)
• multiple copy number alterations in chromosome regions implicated in malignancy progression and indicated a strong expression of MAP2K4 and MCL1 genes in rhabdomyosarcoma (PMID:19012245)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	map2k4a	ENSDARG00000063583
danio_rerio	map2k4b	ENSDARG00000077177
mus_musculus	Map2k4	ENSMUSG00000033352
rattus_norvegicus	Map2k4	ENSRNOG00000003834
drosophila_melanogaster	Mkk4	FBGN0024326
caenorhabditis_elegans		WBGENE00003368
caenorhabditis_elegans		WBGENE00012162

Paralogs (8): MAP2K7 (ENSG00000076984), MAP3K4 (ENSG00000085511), MAP2K2 (ENSG00000126934), NEK1 (ENSG00000137601), MAP2K5 (ENSG00000137764), MAP2K1 (ENSG00000169032), MAP3K2 (ENSG00000169967), MAP3K3 (ENSG00000198909)

Protein

Protein identifiers

Dual specificity mitogen-activated protein kinase kinase 4 — P45985 (reviewed: P45985)

Alternative names: JNK-activating kinase 1, MAPK/ERK kinase 4, SAPK/ERK kinase 1, Stress-activated protein kinase kinase 1, c-Jun N-terminal kinase kinase 1

All UniProt accessions (5): P45985, J3QLE2, K7EP58, R4GN37, R4GN68

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to pro-inflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.

Subunit / interactions. Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.

Post-translational modifications. Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).

Activity regulation. Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.

Domain organisation. The DVD domain (residues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation. The D domain (residues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P45985-1	1	yes
P45985-2	2

RefSeq proteins (2): NP_001268364, NP_003001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.12.2 — mitogen-activated protein kinase kinase (BRENDA: 38 organisms, 149 substrates, 134 inhibitors, 6 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0533	1
ERK2	0.0002	1
K52R-[ERK2]	0.0001	1
K53M-[P38ALPHA]	0.0002	1
P38ALPHA	0.0002	1

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (57 total): strand 17, helix 11, modified residue 6, sequence variant 6, sequence conflict 3, region of interest 3, site 2, binding site 2, initiator methionine 1, chain 1, splice variant 1, domain 1, turn 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3ALN	X-RAY DIFFRACTION	2.3
8YP5	X-RAY DIFFRACTION	2.5
3ALO	X-RAY DIFFRACTION	2.6
3VUT	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45985-F1	78.39	0.50

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 (3): 45–46 (cleavage; by anthrax lethal factor); 58–59 (cleavage; by anthrax lethal factor); 229 (proton acceptor)

Ligand- & substrate-binding residues (2): 108–116; 131

Post-translational modifications (6): 2, 58, 58, 90, 257, 261

Function

Pathways and Gene Ontology

Reactome pathways

37 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-5684264	MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-2262752	Cellular responses to stress
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-2559583	Cellular Senescence
R-HSA-446652	Interleukin-1 family signaling
R-HSA-448424	Interleukin-17 signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-450294	MAP kinase activation
R-HSA-5339562	Uptake and actions of bacterial toxins
R-HSA-5663205	Infectious disease

MSigDB gene sets: 330 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, chr17p12, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, KEGG_MAPK_SIGNALING_PATHWAY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GCAAGGA_MIR502, TATTATA_MIR374, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_CELLULAR_SENESCENCE, BROWNE_HCMV_INFECTION_12HR_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (13): MAPK cascade (GO:0000165), signal transduction (GO:0007165), JNK cascade (GO:0007254), response to wounding (GO:0009611), smooth muscle cell apoptotic process (GO:0034390), intrinsic apoptotic signaling pathway in response to hydrogen peroxide (GO:0036481), Fc-epsilon receptor signaling pathway (GO:0038095), cellular response to mechanical stimulus (GO:0071260), cellular senescence (GO:0090398), negative regulation of motor neuron apoptotic process (GO:2000672), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), cellular response to stress (GO:0033554)

GO Molecular Function (12): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), JUN kinase kinase activity (GO:0008545), molecular adaptor activity (GO:0060090), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Toll-like Receptor Cascades	6
MAP kinase activation	2
Immune System	2
Toll Like Receptor 4 (TLR4) Cascade	2
Toll Like Receptor 2 (TLR2) Cascade	2
Cellular Senescence	1
Fc epsilon receptor (FCERI) signaling	1
Uptake and actions of bacterial toxins	1
Interleukin-1 signaling	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
cellular process	2
cellular response to stimulus	2
MAPK cascade	2
response to stress	2
binding	2
cellular anatomical structure	2
intracellular signaling cassette	1
cell communication	1
signaling	1
regulation of cellular process	1
muscle cell apoptotic process	1
intrinsic apoptotic signaling pathway in response to oxidative stress	1
hydrogen peroxide-mediated programmed cell death	1
Fc receptor signaling pathway	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
cellular response to stress	1
negative regulation of neuron apoptotic process	1
motor neuron apoptotic process	1
regulation of motor neuron apoptotic process	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine/tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
MAP kinase kinase activity	1
JNK cascade	1
molecular_function	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1

Protein interactions and networks

STRING

1820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K4	ARRB2	P32121	971
MAP2K4	MAP3K5	Q99683	938
MAP2K4	JUN	P05412	894
MAP2K4	MAPK8	P45983	892
MAP2K4	MAPK8IP3	Q9UPT6	714
MAP2K4	MAPK14	Q16539	705
MAP2K4	MAP3K11	Q16584	697
MAP2K4	MCL1	Q07820	674
MAP2K4	MAP3K1	Q13233	673
MAP2K4	RIBC2	Q9H4K1	662
MAP2K4	FLNA	P21333	659
MAP2K4	TNF	P01375	638
MAP2K4	AGT	P01019	633
MAP2K4	BCL2	P10415	629
MAP2K4	FLNB	O75369	621

IntAct

38 interactions, top by confidence:

A	B	Type	Score
MAPK9	WDR62	psi-mi:“MI:0914”(association)	0.800
MAPK9	MAPK8	psi-mi:“MI:0914”(association)	0.770
MAP2K4	MAPK8	psi-mi:“MI:0407”(direct interaction)	0.760
MAPK8	WDR62	psi-mi:“MI:0914”(association)	0.730
MAPK9	MAP2K4	psi-mi:“MI:0915”(physical association)	0.660
MAP2K4	MAP3K1	psi-mi:“MI:0915”(physical association)	0.600
MAP3K1	MAP2K4	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
MAP3K1	MAP2K4	psi-mi:“MI:0915”(physical association)	0.600
MAP2K4	ARRB1	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K4	ARRB2	psi-mi:“MI:0407”(direct interaction)	0.440
TRIB1	MAP2K4	psi-mi:“MI:0915”(physical association)	0.400
CFLAR	MAP2K4	psi-mi:“MI:0915”(physical association)	0.400
Arrb2	MAP2K4	psi-mi:“MI:0915”(physical association)	0.400
	MAP2K4	psi-mi:“MI:0915”(physical association)	0.400
MAP2K4		psi-mi:“MI:0915”(physical association)	0.370
RBBP8	MAP2K4	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	MAP2K4	psi-mi:“MI:0915”(physical association)	0.370
MAP2K4	CYLC2	psi-mi:“MI:0915”(physical association)	0.370
FBP2	MAP2K4	psi-mi:“MI:0915”(physical association)	0.370
MAP2K4	STX17	psi-mi:“MI:0915”(physical association)	0.370
STK4	EIF3CL	psi-mi:“MI:0914”(association)	0.350
MAPK8	MAP2K7	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
MAPK8	PRPF4	psi-mi:“MI:0914”(association)	0.350
MAP2K4	PRKCZ	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
BLNK	PLCG2	psi-mi:“MI:0914”(association)	0.350

BioGRID (135): FLNC (Two-hybrid), MAP2K4 (Biochemical Activity), NBR1 (Affinity Capture-Western), MAP3K3 (Affinity Capture-Western), MAP2K4 (Affinity Capture-Western), NBR1 (Reconstituted Complex), MAP3K3 (Reconstituted Complex), KTI12 (Co-fractionation), VASP (Co-fractionation), FLNB (Affinity Capture-Western), MAP2K4 (Biochemical Activity), MAP2K4 (Affinity Capture-Western), MAP2K4 (Affinity Capture-MS), MAP2K4 (Biochemical Activity), MAP2K4 (Reconstituted Complex)

ESM2 similar proteins: A0A5B9GBF0, A1CPG7, A1D2C9, A1IVT7, A2BD05, A2QRF6, B0XR80, D3ZBE5, G1XJZ4, G5EDF7, G5EFM9, M1T7M3, O09110, O75716, O88697, P0CP69, P21708, P26696, P27361, P28482, P45985, P46196, P46734, P47809, P52564, P57760, P59895, P70236, Q0D0P5, Q0U4L8, Q1DUU8, Q1KTF2, Q2WFL5, Q4PC06, Q4W6D3, Q4WSF6, Q52PH6, Q56R42, Q5E9X2, Q63844

Diamond homologs: A0A194VNL2, A0A1S4CGX4, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, A9RWC9, A9S5R3, A9SR33, B0XPE4, C4YLK8, E1BK52, F1NBT0, G4N6Z6, G4NEB8, G5EDF7, O00506, O09110, O14733, O54748, O80396, O94804, O95819, P06784, P08018, P0CY25, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

52 interactions.

A	Effect	B	Mechanism
MAP2K4	up-regulates	MAPK10	phosphorylation
MAP3K2	“up-regulates activity”	MAP2K4	phosphorylation
MAP3K11	up-regulates	MAP2K4	phosphorylation
MAP3K8	up-regulates	MAP2K4	phosphorylation
MAP2K4	up-regulates	MAPK9	phosphorylation
MAP2K4	“up-regulates activity”	JNK	phosphorylation
MAP3K1	“up-regulates activity”	MAP2K4	phosphorylation
AKT1	down-regulates	MAP2K4	phosphorylation
MAP3K20	“up-regulates activity”	MAP2K4	phosphorylation
AKT	down-regulates	MAP2K4	phosphorylation
MAP2K4	“up-regulates activity”	MAPK8	phosphorylation
FLNA	“up-regulates activity”	MAP2K4	binding
3b	“up-regulates activity”	MAP2K4
MAP2K4	“up-regulates activity”	MAPK13	phosphorylation
AKT	“down-regulates activity”	MAP2K4	phosphorylation
SRMS	“down-regulates activity”	MAP2K4	phosphorylation
MAP3K10	“up-regulates activity”	MAP2K4	phosphorylation
MAP2K4	“up-regulates activity”	JUN	phosphorylation
MAP3K12	“up-regulates activity”	MAP2K4	phosphorylation
MAP2K4	“up-regulates activity”	MAPK14	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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
FCERI mediated MAPK activation	6	74.2×	4e-08
Signaling by ALK fusions and activated point mutants	5	26.8×	2e-04
Toll Like Receptor 4 (TLR4) Cascade	5	23.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
Fc-epsilon receptor signaling pathway	6	141.8×	1e-09
positive regulation of ERK1 and ERK2 cascade	6	16.5×	3e-04
protein phosphorylation	5	11.0×	5e-03
positive regulation of gene expression	6	7.5×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 8 cancer types — BRCA, CHOL, COADREAD, EGC, ESCC, HCC, PAAD, PANCREAS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2940 predictions. Top by Δscore:

Variant	Effect	Δscore
17:12021000:GG:G	donor_gain	1.0000
17:12021001:GG:G	donor_gain	1.0000
17:12054883:TCTCA:T	acceptor_loss	1.0000
17:12054884:CTCA:C	acceptor_loss	1.0000
17:12054885:TCA:T	acceptor_loss	1.0000
17:12054886:CAGGT:C	acceptor_loss	1.0000
17:12054888:G:GC	acceptor_loss	1.0000
17:12054988:ACAT:A	donor_gain	1.0000
17:12054988:ACATG:A	donor_loss	1.0000
17:12054989:CAT:C	donor_gain	1.0000
17:12054990:ATGTG:A	donor_loss	1.0000
17:12054991:TG:T	donor_loss	1.0000
17:12054992:G:C	donor_loss	1.0000
17:12054992:G:GG	donor_gain	1.0000
17:12054994:GAGTA:G	donor_loss	1.0000
17:12077008:A:T	donor_gain	1.0000
17:12095569:TTCCA:T	acceptor_loss	1.0000
17:12095570:TCCA:T	acceptor_loss	1.0000
17:12095572:CAGA:C	acceptor_loss	1.0000
17:12095573:A:AG	acceptor_gain	1.0000
17:12095573:AGAG:A	acceptor_loss	1.0000
17:12095574:G:GA	acceptor_loss	1.0000
17:12095574:G:GG	acceptor_gain	1.0000
17:12095574:GA:G	acceptor_gain	1.0000
17:12095574:GAGA:G	acceptor_gain	1.0000
17:12095633:T:TA	donor_gain	1.0000
17:12095634:A:AA	donor_gain	1.0000
17:12095690:GAGAG:G	donor_gain	1.0000
17:12095691:AGAGG:A	donor_loss	1.0000
17:12095693:AGGTA:A	donor_loss	1.0000

AlphaMissense

2644 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:12081391:G:A	G85E	1.000
17:12081397:T:C	L87P	1.000
17:12081442:T:C	L102S	1.000
17:12081462:G:A	G109R	1.000
17:12081462:G:C	G109R	1.000
17:12081463:G:A	G109E	1.000
17:12081463:G:T	G109V	1.000
17:12081466:G:C	R110P	1.000
17:12081468:G:A	G111R	1.000
17:12081468:G:C	G111R	1.000
17:12081469:G:A	G111E	1.000
17:12081469:G:C	G111A	1.000
17:12081469:G:T	G111V	1.000
17:12081477:G:C	G114R	1.000
17:12081477:G:T	G114C	1.000
17:12081478:G:A	G114D	1.000
17:12081478:G:T	G114V	1.000
17:12081483:G:C	V116L	1.000
17:12081483:G:T	V116F	1.000
17:12081484:T:A	V116D	1.000
17:12081484:T:C	V116A	1.000
17:12081522:G:C	A129P	1.000
17:12081523:C:A	A129E	1.000
17:12081526:T:A	V130D	1.000
17:12081528:A:C	K131Q	1.000
17:12081528:A:G	K131E	1.000
17:12081529:A:T	K131I	1.000
17:12081530:A:C	K131N	1.000
17:12081530:A:T	K131N	1.000
17:12095577:A:C	R132S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001575 (17:12030828 T>A), RS1000002671 (17:12021906 G>A), RS1000076372 (17:12078439 T>C), RS1000079282 (17:12114230 G>A), RS1000154446 (17:12071045 A>C,G), RS1000178205 (17:12131455 C>T), RS1000218204 (17:12139142 A>G), RS1000235819 (17:12045767 T>C), RS1000255381 (17:12045196 A>C,T), RS1000270544 (17:12138883 C>A), RS1000278495 (17:12097909 A>G), RS1000291097 (17:12100636 A>G), RS1000323258 (17:12055578 A>G), RS1000326128 (17:12094040 T>C), RS1000336391 (17:12133578 T>G)

Disease associations

OMIM: gene MIM:601335 | disease phenotypes:

GenCC curated gene-disease

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), neurodevelopmental disorder (MONDO:0700092), neuroblastoma (MONDO:0005072)

Orphanet (1): Neuroblastoma (Orphanet:635)

HPO phenotypes

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

GWAS associations

104 associations (top):

Study	Trait	p-value
GCST001651_86	Response to amphetamines	5.000000e-06
GCST008058_27	Estimated glomerular filtration rate	4.000000e-11
GCST010042_23	Asthma	9.000000e-10
GCST010043_32	Asthma	1.000000e-08
GCST010796_1626	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_1627	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10
GCST010796_1628	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_1629	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_1630	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1680	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-14
GCST010796_1681	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-14
GCST010796_1682	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-14
GCST010796_1683	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_1684	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-14
GCST010796_1685	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-15
GCST010796_1686	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-15
GCST010796_1687	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-14
GCST010796_1688	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_1689	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-14
GCST010796_1690	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14
GCST010796_1691	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-14
GCST010796_1692	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_1693	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-13
GCST010796_1694	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_1695	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-12
GCST010796_1696	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-12
GCST010796_1697	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-12
GCST010796_1698	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST010796_1699	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_1700	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2897 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 227,428 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL230011	TG100-115	2	1,504
CHEMBL44	GENISTEIN	2	44,212
CHEMBL475251	R-406	2	762
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2159140	Toxicity	3	ethanol	Alcohol abuse;Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2159140	MAP2K4	3	1.75	1	ethanol

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE7 family

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

Ligand	Action	Affinity	Parameter
staurosporine	Inhibition	9.0	pIC50
compound 39 [PMID: 40643363]	Inhibition	7.11	pIC50
darizmetinib	Inhibition	6.3	pIC50
MEK inhibitor I	Inhibition	6.0	pIC50
compound 11 [PMID: 26431428]	Inhibition	5.3	pIC50

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM

ChEMBL bioactivities

223 potent at pChembl≥5 of 227 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.82	Kd	1.5	nM	CHEMBL4865410
8.77	Kd	1.7	nM	CHEMBL4798975
8.42	Kd	3.8	nM	LESTAURTINIB
7.54	IC50	29	nM	CHEMBL4790247
7.39	IC50	41	nM	CHEMBL4758063
7.22	IC50	60	nM	CHEMBL6062934
7.21	IC50	61	nM	CHEMBL4879048
7.20	IC50	63	nM	CHEMBL5923880
7.18	IC50	66	nM	CHEMBL4758063
7.16	Kd	70	nM	STAUROSPORINE
7.08	IC50	83	nM	CHEMBL4866649
7.05	IC50	89	nM	CHEMBL4784779
7.02	IC50	96	nM	CHEMBL4848865
7.00	IC50	100	nM	CHEMBL5777804
7.00	IC50	100	nM	CHEMBL4758063
6.96	IC50	110	nM	CHEMBL5876616
6.92	IC50	120	nM	CHEMBL6010398
6.89	IC50	130	nM	CHEMBL6062934
6.88	IC50	132	nM	CHEMBL5086263
6.84	Kd	146	nM	TOVORAFENIB
6.84	IC50	146	nM	CHEMBL4798975
6.82	IC50	150	nM	CHEMBL5755015
6.82	Kd	150	nM	TAE-684
6.76	IC50	173	nM	CHEMBL5093741
6.75	IC50	180	nM	CHEMBL5897699
6.75	IC50	180	nM	CHEMBL5755015
6.72	IC50	190	nM	CHEMBL4748767
6.72	Kd	190	nM	PLX-4720
6.70	IC50	200	nM	CHEMBL5770842
6.70	Kd	200	nM	R-406
6.68	IC50	210	nM	CHEMBL5801861
6.66	IC50	220	nM	CHEMBL5755015
6.62	IC50	240	nM	CHEMBL6043204
6.60	IC50	250	nM	CHEMBL6043204
6.60	Kd	250	nM	KW-2449
6.58	IC50	260	nM	CHEMBL5923880
6.55	IC50	281	nM	CHEMBL5278864
6.54	IC50	290	nM	CHEMBL4865159
6.51	IC50	310	nM	CHEMBL4849172
6.51	IC50	310	nM	CHEMBL4872723
6.48	Kd	330	nM	CHEMBL386051
6.44	IC50	360	nM	CHEMBL5777804
6.42	IC50	380	nM	CHEMBL4858450
6.41	Kd	390	nM	CHEMBL2425628
6.41	IC50	390	nM	CHEMBL4846360
6.41	IC50	390	nM	CHEMBL5917662
6.40	IC50	400	nM	GENISTEIN
6.39	IC50	410	nM	CHEMBL5876616
6.39	IC50	410	nM	CHEMBL5801861
6.38	IC50	420	nM	CHEMBL4874017

PubChem BioAssay actives

87 with measured affinity, of 643 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
(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	126758: Inhibition of Mitogen activated protein kinase kinase 4	ic50	0.0010	uM
N-[3-[5-(4-aminophenyl)-2H-pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-1-phenylmethanesulfonamide	1753617: Binding affinity to wild-type human partial length MKK4 (S84 to D399 residues) expressed in mammalian expression system by Kinomescan method	kd	0.0015	uM
4-[3-[3-(benzylsulfonylamino)-2,6-difluorobenzoyl]-2H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide	1753617: Binding affinity to wild-type human partial length MKK4 (S84 to D399 residues) expressed in mammalian expression system by Kinomescan method	kd	0.0017	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	507615: Binding affinity to MEK4	kd	0.0038	uM
N-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-2H-pyrazolo[3,4-b]pyridin-5-yl]phenyl]sulfonylacetamide	1753620: Inhibition of MKK4 (unknown origin) by PanQinase assay	ic50	0.0290	uM
4-(6-fluoro-1H-indazol-3-yl)benzoic acid	1720292: Inhibition of MEK4 (unknown origin)	ic50	0.0410	uM
4-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.0610	uM
4-[[3-(6-fluoro-1H-indazol-3-yl)phenyl]sulfonylamino]benzamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.0830	uM
4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-2H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide	1753620: Inhibition of MKK4 (unknown origin) by PanQinase assay	ic50	0.0890	uM
3-(6-fluoro-1H-indazol-3-yl)benzoic acid	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.0960	uM
22-fluoro-10,14-dimethyl-9-oxo-3-(trifluoromethyl)-4,5,10,13,14,19,21-heptazapentacyclo[15.5.2.12,5.012,16.020,23]pentacosa-1(22),2(25),3,12,15,17(24),18,20(23)-octaene-15-carbonitrile	1823464: Inhibition of MEK4 (unknown origin) at 1 uM by kinome scan method	ic50	0.1320	uM
Tovorafenib	1425041: 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	0.1460	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624902: Binding constant for MEK4 kinase domain	kd	0.1500	uM
10,14-dimethyl-9-oxo-3-(trifluoromethyl)-4,5,10,13,14,19,21-heptazapentacyclo[15.5.2.12,5.012,16.020,23]pentacosa-1(22),2(25),3,12,15,17(24),18,20(23)-octaene-15-carbonitrile	1823464: Inhibition of MEK4 (unknown origin) at 1 uM by kinome scan method	ic50	0.1730	uM
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	624902: Binding constant for MEK4 kinase domain	kd	0.1900	uM
4-(1H-indazol-3-yl)benzoic acid	1720292: Inhibition of MEK4 (unknown origin)	ic50	0.1900	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	624902: Binding constant for MEK4 kinase domain	kd	0.2000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624902: Binding constant for MEK4 kinase domain	kd	0.2500	uM
(Z)-2-cyano-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]prop-2-enamide	1928588: Inhibition of MAP2K4 (unknown origin) at 100 uM preincubated for 1 hr followed by substrate addition and measured after 1 hr by Z-lyte assay relative to control	ic50	0.2810	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(4-methylsulfonylphenyl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.2900	uM
6-fluoro-3-phenyl-1H-indazole	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.3100	uM
3-(6-fluoro-1H-indazol-3-yl)-N-phenylbenzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.3100	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624902: Binding constant for MEK4 kinase domain	kd	0.3300	uM
N-cyclopropyl-3-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.3800	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(4-methoxyphenyl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.3900	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769505: Binding affinity to MEK4 (unknown origin)	kd	0.3900	uM
Genistein	1720289: Inhibition of recombinant human MEK4 (14 to 377 residues) after 5 mins by Western blot analysis	ic50	0.4000	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(2-methoxyphenyl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.4200	uM
3-(6-fluoro-1H-indazol-3-yl)-N-pyridin-3-ylbenzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.4500	uM
N-(4-cyanophenyl)-3-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.4700	uM
N-[4-(6-fluoro-1H-indazol-3-yl)phenyl]methanesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.4800	uM
Pazopanib	435822: Binding constant for MEK4 kinase domain	kd	0.5900	uM
2,2,2-trifluoro-1-[4-(6-fluoro-1H-indazol-3-yl)phenyl]ethanone	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.6000	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(4-sulfamoylphenyl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.6200	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435822: Binding constant for MEK4 kinase domain	kd	0.6300	uM
Sunitinib	624902: Binding constant for MEK4 kinase domain	kd	0.7000	uM
N-[4-(6-fluoro-1H-indazol-3-yl)phenyl]pyridine-3-sulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.7500	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624902: Binding constant for MEK4 kinase domain	kd	0.8100	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(3-fluoro-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1895126: Inhibition of human MAP2K4 by radiometric PanQinase activity assay	ic50	0.8300	uM
N-cyclohexyl-3-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.8600	uM
N-(4-acetylphenyl)-3-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.8600	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(4-fluorophenyl)benzenesulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.8800	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624902: Binding constant for MEK4 kinase domain	kd	0.9100	uM
4-[4-[2-(cyclopentylamino)pyrimidin-4-yl]-1H-pyrazol-5-yl]cyclohexan-1-ol	353928: Inhibition of MKK4	ic50	0.9200	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	435822: Binding constant for MEK4 kinase domain	kd	0.9300	uM
2-[3-[2-[[(3S)-1-(cyclopropanecarbonyl)piperidin-3-yl]amino]pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile	2031924: Inhibition of MKK4 (unknown origin) assessed as incorporation of 33P-ATP	ic50	0.9700	uM
4-phenyl-9H-pyrimido[4,5-b]indole-6-carboxamide	1863528: Inhibition of MKK4 (unknown origin)	ic50	1.0000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624902: Binding constant for MEK4 kinase domain	kd	1.0000	uM
Palbociclib	1425041: 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	1.2510	uM
N-[3-(6-fluoro-1H-indazol-3-yl)phenyl]pyridine-3-sulfonamide	1780567: Inhibition of human recombinant full length N-terminal GST tagged MEK4 expressed in Sf21 cells using p38 alpha as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Quercetin	affects cotreatment, increases expression, decreases reaction, increases phosphorylation, increases response to substance (+1 more)	4
sodium arsenite	affects reaction, increases expression, decreases reaction, decreases expression	3
Arsenic Trioxide	increases reaction, increases phosphorylation, increases response to substance, decreases reaction, increases activity (+1 more)	3
Doxorubicin	decreases response to substance, affects activity, increases expression	3
bisphenol A	increases methylation, decreases expression	2
Glyphosate	affects methylation, decreases expression	2
Benzo(a)pyrene	increases phosphorylation, increases methylation	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Particulate Matter	decreases reaction, increases abundance, increases phosphorylation	2
aristolochic acid I	decreases expression	1
Asian ginseng	decreases reaction, increases abundance, increases phosphorylation	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	decreases response to substance	1
sulforaphane	increases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
mangostin	increases phosphorylation	1
sulindac sulfone	increases activity, increases phosphorylation	1
andrographolide	decreases reaction, increases phosphorylation	1
cadmium sulfate	increases abundance, increases phosphorylation, decreases reaction	1
diallyl trisulfide	affects reaction, increases abundance, increases degradation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
cisplatin-DNA adduct	increases activity	1
licochalcone A	decreases phosphorylation, increases reaction	1

ChEMBL screening assays

255 unique, capped per target: 255 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000441	Binding	Inhibition of human MKK4/7 expressed in baculovirus insect cell system	Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. — J Med Chem

Cellosaurus cell lines

35 cell lines: 35 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0152	AsPC-1	Cancer cell line	Female
CVCL_0237	Capan-1	Cancer cell line	Male
CVCL_0617	MDA-MB-134-VI	Cancer cell line	Female
CVCL_0621	MDA-MB-415	Cancer cell line	Female
CVCL_0A59	Capan1M9	Cancer cell line	Male
CVCL_1183	DU4475	Cancer cell line	Female
CVCL_1451	NCC-IT	Cancer cell line	Male
CVCL_1589	NCI-H774	Cancer cell line	Male
CVCL_1717	SW1417	Cancer cell line	Female
CVCL_2022	DND-41	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT06047535	PHASE4	NOT_YET_RECRUITING	Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Combined With Isotretinoin for Maintenance Treatment of Patients With High-Risk Neuroblastoma in First Complete Response.
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00002802	PHASE3	COMPLETED	Therapy Based on Stage of Disease and Risk Assessment in Treating Children With Neuroblastoma
NCT00003093	PHASE3	COMPLETED	Combination Chemotherapy in Treating Children With Neuroblastoma
NCT00003119	PHASE3	COMPLETED	Surgery in Treating Children With Neuroblastoma
NCT00004188	PHASE3	COMPLETED	Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma
NCT00025428	PHASE3	COMPLETED	Combination Chemotherapy Before Surgery in Treating Children With Localized Neuroblastoma
NCT00026312	PHASE3	COMPLETED	Isotretinoin With or Without Dinutuximab, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma
NCT00030719	PHASE3	UNKNOWN	Combination Chemotherapy With or Without Filgrastim Before Surgery, High-Dose Chemotherapy, and Radiation Therapy Followed by Isotretinoin With or Without Monoclonal Antibody in Treating Patients With Neuroblastoma
NCT00033293	PHASE3	COMPLETED	Cyclophosphamide and Prednisone With or Without Immunoglobulin in Treating Abnormal Muscle Movement in Children With Neuroblastoma
NCT00126412	PHASE3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT00276731	PHASE3	UNKNOWN	Combination Chemotherapy Followed By Surgery With or Without Radiation Therapy in Treating Young Patients With Stage II or Stage III Neuroblastoma
NCT00324324	PHASE3	TERMINATED	Moxifloxacin in Preventing Bacterial Infections in Patients Who Have Undergone Donor Stem Cell Transplant
NCT00365755	PHASE3	COMPLETED	Combination Chemotherapy in Treating Young Patients Who Are Undergoing Surgery and an Autologous Bone Marrow Transplant for Disseminated Neuroblastoma
NCT00410631	PHASE3	UNKNOWN	Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma
NCT00416676	PHASE3	UNKNOWN	Combination Chemotherapy and Surgery With or Without Radiation Therapy in Treating Patients With Stage 2 or Stage 3 Neuroblastoma
NCT00417053	PHASE3	UNKNOWN	Combination Chemotherapy in Treating Infants With Newly Diagnosed Neuroblastoma Who Are Undergoing Surgery With or Without Autologous Bone Marrow or Peripheral Stem Cell Transplant
NCT00499616	PHASE3	COMPLETED	Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma
NCT00567567	PHASE3	COMPLETED	Comparing Two Different Myeloablation Therapies in Treating Young Patients Who Are Undergoing a Stem Cell Transplant for High-Risk Neuroblastoma
NCT00716976	PHASE3	COMPLETED	Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy
NCT00782145	PHASE3	COMPLETED	A Web-Based Stem Cell Transplant Support System or Standard Care in Young Patients Undergoing Stem Cell Transplant and Their Families
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT01704716	PHASE3	RECRUITING	High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
NCT01868269	PHASE3	COMPLETED	Opsoclonus Myoclonus Syndrome/Dancing Eye Syndrome (OMS/DES) in Children With and Without Neuroblastoma (NBpos and NBneg)Opsoclonus Myoclonus Syndrome/Dancing Eye Syndrome (OMS/DES) in Children With and Without Neuroblastoma (NBpos and NBneg)
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT02176967	PHASE3	ACTIVE_NOT_RECRUITING	Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma
NCT03042416	PHASE3	COMPLETED	18F-DOPA PET Imaging: an Evaluation of Biodistribution and Safety
NCT03042429	PHASE3	COMPLETED	Combination Chemotherapy Followed by Stem Cell Transplant in High-risk Neuroblastoma Patients
NCT03126916	PHASE3	RECRUITING	Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)
NCT04706910	PHASE3	RECRUITING	18F-DOPA II - PET Imaging Optimization
NCT04724369	PHASE3	ACTIVE_NOT_RECRUITING	Open-Label Study of 18F-mFBG for Imaging Neuroblastoma
NCT06071897	PHASE3	RECRUITING	Induction Chemoimmunotherapy for Patients With High-risk Neuroblastoma