MAP3K15

Summary

MAP3K15 (mitogen-activated protein kinase kinase kinase 15, HGNC:31689) is a protein-coding gene on chromosome Xp22.12, encoding Mitogen-activated protein kinase kinase kinase 15 (Q6ZN16). Serine/threonine kinase which acts as a component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAPK) family. These family members function in a protein kinase signal transduction cascade, where an activated MAPK kinase kinase (MAP3K) phosphorylates and activates a specific MAPK kinase (MAP2K), which then activates a specific MAPK. This MAP3K protein plays an essential role in apoptotic cell death triggered by cellular stresses.

Source: NCBI Gene 389840 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 395 total — 1 pathogenic
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001001671

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31689
Approved symbol	MAP3K15
Name	mitogen-activated protein kinase kinase kinase 15
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	bA723P2.3, FLJ16518, ASK3
Ensembl gene	ENSG00000180815
Ensembl biotype	protein_coding
OMIM	300820
Entrez	389840

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000338883, ENST00000359173, ENST00000470101, ENST00000518578, ENST00000927252, ENST00000927253, ENST00000947404, ENST00000947405, ENST00000947406

RefSeq mRNA: 1 — MANE Select: NM_001001671 NM_001001671

CCDS: CCDS35212

Canonical transcript exons

ENST00000338883 — 29 exons

Exon	Start	End
ENSE00001402289	19514901	19515508
ENSE00001412536	19488828	19488967
ENSE00001482559	19486482	19486505
ENSE00001849881	19360059	19360833
ENSE00003460913	19361339	19361415
ENSE00003467452	19373536	19373695
ENSE00003489535	19409924	19409973
ENSE00003493292	19415107	19415257
ENSE00003498759	19392343	19392473
ENSE00003512109	19371345	19371530
ENSE00003512650	19413357	19413464
ENSE00003522239	19398226	19398359
ENSE00003558343	19425531	19425690
ENSE00003561456	19400576	19400663
ENSE00003562648	19456913	19457019
ENSE00003564566	19361493	19361593
ENSE00003569738	19362738	19362850
ENSE00003580545	19392002	19392107
ENSE00003609844	19374477	19374660
ENSE00003617646	19369054	19369219
ENSE00003630043	19426231	19426343
ENSE00003641420	19372653	19372827
ENSE00003651483	19431438	19431608
ENSE00003670311	19407188	19407283
ENSE00003671688	19464213	19464406
ENSE00003672039	19370959	19371064
ENSE00003674486	19395081	19395208
ENSE00003675100	19380120	19380277
ENSE00003691907	19459985	19460153

Expression profiles

Bgee: expression breadth ubiquitous, 108 present calls, max score 93.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2899 / max 43.6520, expressed in 136 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198615	0.1658	83
198614	0.1241	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	93.33	gold quality
right adrenal gland cortex	UBERON:0035827	89.88	gold quality
right adrenal gland	UBERON:0001233	89.59	gold quality
left adrenal gland cortex	UBERON:0035825	89.28	gold quality
left adrenal gland	UBERON:0001234	88.74	gold quality
adrenal gland	UBERON:0002369	87.86	gold quality
islet of Langerhans	UBERON:0000006	78.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.24	silver quality
spleen	UBERON:0002106	67.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.80	gold quality
adult mammalian kidney	UBERON:0000082	65.43	gold quality
kidney	UBERON:0002113	63.22	gold quality
pancreas	UBERON:0001264	62.38	gold quality
metanephros cortex	UBERON:0010533	61.81	gold quality
pituitary gland	UBERON:0000007	61.72	gold quality
adenohypophysis	UBERON:0002196	61.07	gold quality
ganglionic eminence	UBERON:0004023	60.14	gold quality
cortex of kidney	UBERON:0001225	60.06	gold quality
bone marrow	UBERON:0002371	59.66	gold quality
cortical plate	UBERON:0005343	59.05	gold quality
stromal cell of endometrium	CL:0002255	58.80	gold quality
ventricular zone	UBERON:0003053	58.43	silver quality
bone marrow cell	CL:0002092	57.73	gold quality
ovary	UBERON:0000992	55.39	gold quality
left ovary	UBERON:0002119	54.92	gold quality
body of pancreas	UBERON:0001150	54.08	gold quality
right ovary	UBERON:0002118	53.96	gold quality
hypothalamus	UBERON:0001898	53.83	gold quality
cerebellar hemisphere	UBERON:0002245	53.82	gold quality
cerebellar cortex	UBERON:0002129	53.76	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.81
E-MTAB-6058	no	99.30
E-MTAB-6142	no	27.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting MAP3K15, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-4716-5P	98.82	68.57	1168

Literature-anchored findings (GeneRIF, showing 5)

• “ASK3 gene” is a novel member of apoptosis signal-regulating kinases and that it plays a pivotal role in the signal transduction pathway implicated in apoptotic cell death triggered by cellular stresses. (PMID:20362554)
• ASK3 controls both RVD and RVI under osmotic stress. (PMID:29539411)
• Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases. (PMID:32156783)
• Macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. (PMID:33649309)
• Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes. (PMID:36383675)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k15	ENSDARG00000013310
mus_musculus	Map3k15	ENSMUSG00000031303
rattus_norvegicus	Map3k15	ENSRNOG00000025290
drosophila_melanogaster	Ask1	FBGN0014006
caenorhabditis_elegans		WBGENE00003822

Paralogs (2): MAP3K6 (ENSG00000142733), MAP3K5 (ENSG00000197442)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 15 — Q6ZN16 (reviewed: Q6ZN16)

Alternative names: Apoptosis signal-regulating kinase 3, MAPK/ERK kinase kinase 15

All UniProt accessions (2): Q6ZN16, A0A140T8W5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as a component of the MAP kinase signal transduction pathway. Once activated, acts as an upstream activator of the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases. May function in a signal transduction pathway that is activated by various cell stresses and leads to apoptosis. Involved in phosphorylation of WNK4 in response to osmotic stress or hypotonic low-chloride stimulation via the p38 MAPK signal transduction cascade.

Tissue specificity. Isoform 2 and isoform 3 are widely expressed. Isoform 2 highest levels are observed in fetal brain, and isoform 3 highest levels in pancreas, peripheral blood leukocytes, fetal brain and spleen.

Activity regulation. Contains an N-terminal autoinhibitory domain. Activated by phosphorylation at Thr-812, inhibited by phosphorylation at Ser-924 and Ser-994.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q6ZN16-1	1	yes
Q6ZN16-2	2
Q6ZN16-3	3

RefSeq proteins (1): NP_001001671* (*=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
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR025136	MAP3K_TRAF-bd	Domain
IPR043969	MAP3K_PH	Domain
IPR046872	DRHyd-ASK	Domain
IPR046873	HisK-N-like	Domain

Pfam: PF00069, PF13281, PF19039, PF20302, PF20309

Catalyzed reactions (Rhea), 2 shown:

• 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 (35 total): sequence variant 13, helix 5, splice variant 3, compositionally biased region 3, binding site 2, region of interest 2, chain 1, domain 1, modified residue 1, mutagenesis site 1, sequence conflict 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6V0M	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZN16-F1	75.41	0.29

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): 773 (proton acceptor)

Ligand- & substrate-binding residues (2): 681; 658–666

Post-translational modifications (1): 994

Mutagenesis-validated functional residues (1):

Position	Phenotype
681	abolished protein kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 39 (showing top): TGCTGAY_UNKNOWN, GOBP_JNK_CASCADE, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_MAP_KINASE_KINASE_KINASE_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, CHEN_METABOLIC_SYNDROM_NETWORK, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, CHYLA_CBFA2T3_TARGETS_UP, chrXp22, GOBP_P38MAPK_CASCADE, CAHOY_OLIGODENDROCUTIC, STK33_DN, STK33_NOMO_DN

GO Biological Process (4): JNK cascade (GO:0007254), p38MAPK cascade (GO:0038066), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468)

GO Molecular Function (9): MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	3
protein kinase activity	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1

Protein interactions and networks

STRING

1063 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K15	FAM47B	Q8NA70	480
MAP3K15	FAS	P25445	430
MAP3K15	OR4D5	Q8NGN0	358
MAP3K15	CCDC185	Q8N715	349
MAP3K15	BEND2	Q8NDZ0	342
MAP3K15	RAI2	Q9Y5P3	339
MAP3K15	SATL1	Q86VE3	327
MAP3K15	OR10G9	Q8NGN4	324
MAP3K15	KIAA1210	Q9ULL0	305
MAP3K15	FAM234A	Q9H0X4	285
MAP3K15	ITIH6	Q6UXX5	278
MAP3K15	VWC2L	B2RUY7	278
MAP3K15	CST9L	Q9H4G1	274
MAP3K15	LRP5L	A4QPB2	272
MAP3K15	LRRC28	Q86X40	271

IntAct

13 interactions, top by confidence:

A	B	Type	Score
TNFSF13B	IPO8	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAE	SRSF10	psi-mi:“MI:0914”(association)	0.560
PRKAB2	PRKAB2	psi-mi:“MI:0914”(association)	0.550
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
MAP3K15	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
CDC37	MAP3K15	psi-mi:“MI:0915”(physical association)	0.400
SYCE3	TRIM24	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
TNFSF13B	TNPO2	psi-mi:“MI:0914”(association)	0.350
cysJ	MAP3K15	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): MAP3K15 (Affinity Capture-MS), RAB10 (Co-fractionation), MAP3K15 (Affinity Capture-MS), MAP3K15 (Affinity Capture-MS), MAP3K15 (Affinity Capture-MS), SSR1 (Affinity Capture-MS), LPCAT1 (Affinity Capture-MS), MAP3K15 (Affinity Capture-MS), NME3 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), SPNS1 (Affinity Capture-MS), RRBP1 (Affinity Capture-MS), SLC7A5 (Affinity Capture-MS), MAP3K15 (Affinity Capture-MS), MAP3K15 (Affinity Capture-MS)

ESM2 similar proteins: A0JN86, A2AHJ4, A2APV2, A2AQW0, A9JRL3, B3DK16, O08874, O35099, P0CF52, P19447, P23798, P25916, P32866, P35226, P35227, P49135, Q07139, Q1JPS1, Q1RMT1, Q21029, Q28H21, Q2YDF9, Q32KX7, Q3UK78, Q4QR06, Q5R8L2, Q5RA62, Q5SDR3, Q5ZKK7, Q640D5, Q6DD21, Q6DLV9, Q6GN16, Q6RI45, Q6ZN16, Q7T3E6, Q7Z569, Q7ZYZ7, Q86SE9, Q8BPM2

Diamond homologs: A0A078CGE6, A0A194W8T8, A2AQW0, A2QHV0, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A7A1P0, A8XJW8, A9RVK2, A9SY39, B0LT89, B0XXN8, B5VNQ3, C4YRB7, E9Q3S4, F4HRJ4, G4N7X0, G4NDR3, H2L099, O00506, O14047, O14305, O22040, O22042, O24527, O54748, O61122, O61125, O81472, O95382, P0CY23, P0CY24, P23561, P27636, P28829

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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
Signaling by Rho GTPases	5	12.2×	6e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	5	12.0×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	220
Likely benign	34
Benign	24

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
816314	GRCh37/hg19 Xp22.2-22.12(chrX:16194993-20640014)x2	Pathogenic

SpliceAI

4784 predictions. Top by Δscore:

Variant	Effect	Δscore
X:19361334:CTTA:C	donor_loss	1.0000
X:19361336:TAC:T	donor_loss	1.0000
X:19361337:A:AC	donor_gain	1.0000
X:19361337:A:AG	donor_loss	1.0000
X:19361338:C:CA	donor_loss	1.0000
X:19361338:C:CC	donor_gain	1.0000
X:19361412:CAAT:C	acceptor_gain	1.0000
X:19361415:TC:T	acceptor_loss	1.0000
X:19361416:C:CC	acceptor_gain	1.0000
X:19361416:CTGA:C	acceptor_loss	1.0000
X:19361488:TTTAC:T	donor_loss	1.0000
X:19361489:TTA:T	donor_loss	1.0000
X:19361490:TA:T	donor_loss	1.0000
X:19361492:C:CT	donor_loss	1.0000
X:19361589:AATAC:A	acceptor_gain	1.0000
X:19361590:ATAC:A	acceptor_gain	1.0000
X:19361591:TAC:T	acceptor_gain	1.0000
X:19361592:AC:A	acceptor_gain	1.0000
X:19361593:CC:C	acceptor_gain	1.0000
X:19361593:CCTG:C	acceptor_loss	1.0000
X:19361594:C:CC	acceptor_gain	1.0000
X:19361594:C:CG	acceptor_loss	1.0000
X:19361600:C:CT	acceptor_gain	1.0000
X:19362736:A:AC	donor_gain	1.0000
X:19362737:C:CC	donor_gain	1.0000
X:19362737:CAATT:C	donor_gain	1.0000
X:19362756:A:C	donor_gain	1.0000
X:19362856:T:C	acceptor_gain	1.0000
X:19362856:T:TC	acceptor_gain	1.0000
X:19369217:GCT:G	acceptor_gain	1.0000

AlphaMissense

8638 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:19398249:T:A	K681N	1.000
X:19398249:T:G	K681N	1.000
X:19371017:G:C	F1114L	0.999
X:19371017:G:T	F1114L	0.999
X:19371019:A:G	F1114L	0.999
X:19380206:A:G	W835R	0.999
X:19380206:A:T	W835R	0.999
X:19392052:C:T	G794E	0.999
X:19392054:A:C	F793L	0.999
X:19392054:A:T	F793L	0.999
X:19392056:A:G	F793L	0.999
X:19392057:A:C	D792E	0.999
X:19392057:A:T	D792E	0.999
X:19392058:T:A	D792V	0.999
X:19392058:T:G	D792A	0.999
X:19392059:C:G	D792H	0.999
X:19392087:G:C	N782K	0.999
X:19392087:G:T	N782K	0.999
X:19392350:T:A	D773V	0.999
X:19392350:T:G	D773A	0.999
X:19392386:A:G	L761P	0.999
X:19395104:A:T	I724K	0.999
X:19395132:A:G	S715P	0.999
X:19395141:A:G	Y712H	0.999
X:19395146:A:T	V710D	0.999
X:19398250:T:A	K681I	0.999
X:19398253:A:T	I680N	0.999
X:19398256:G:T	A679D	0.999
X:19398283:C:G	R670P	0.999
X:19398286:C:T	G669D	0.999

dbSNP variants (sampled 300 via entrez): RS1000036487 (X:19373463 G>A,C), RS1000089099 (X:19493387 A>G), RS1000098749 (X:19426821 A>AAAAAC), RS1000108108 (X:19372950 A>G), RS1000108646 (X:19468892 G>A), RS1000135914 (X:19410115 T>C), RS1000141315 (X:19468683 A>G), RS1000177487 (X:19478519 A>T), RS1000251587 (X:19492837 G>A), RS1000262278 (X:19428291 C>T), RS1000264161 (X:19379765 A>G), RS1000272853 (X:19363137 C>T), RS1000308218 (X:19486293 A>G), RS1000340270 (X:19486021 A>G,T), RS1000352197 (X:19463793 C>T)

Disease associations

OMIM: gene MIM:300820 | disease phenotypes: MIM:312170

GenCC curated gene-disease

Mondo (2): pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1110	Metabolite levels	6.000000e-06
GCST009391_1174	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010448	3-hydroxyphenylacetic acid measurement
EFO:0006524	L-arginine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163127 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 113,878 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE11 family

ChEMBL bioactivities

11 potent at pChembl≥5 of 11 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.60	Kd	2.5	nM	STAUROSPORINE
8.47	Kd	3.4	nM	LESTAURTINIB
6.10	Kd	800	nM	TAE-684
5.96	Kd	1100	nM	RUXOLITINIB
5.92	Kd	1200	nM	SU-014813
5.89	Kd	1300	nM	SUNITINIB
5.85	Kd	1400	nM	NINTEDANIB
5.60	Kd	2500	nM	CHEMBL1908395
5.55	Kd	2800	nM	CRIZOTINIB

PubChem BioAssay actives

11 with measured affinity, of 143 total; 9 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	624801: Binding constant for MAP3K15 kinase domain	kd	0.0025	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	507597: Binding affinity to MAP3K15	kd	0.0034	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	624801: Binding constant for MAP3K15 kinase domain	kd	0.8000	uM
Ruxolitinib	624801: Binding constant for MAP3K15 kinase domain	kd	1.1000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624801: Binding constant for MAP3K15 kinase domain	kd	1.2000	uM
Sunitinib	507597: Binding affinity to MAP3K15	kd	1.3000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624801: Binding constant for MAP3K15 kinase domain	kd	1.4000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624801: Binding constant for MAP3K15 kinase domain	kd	2.5000	uM
Crizotinib	624801: Binding constant for MAP3K15 kinase domain	kd	2.8000	uM

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	decreases expression	1
potassium perchlorate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Methapyrilene	increases methylation	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

81 unique, capped per target: 81 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166056	Binding	Inhibition of MAP3K15 at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg 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_B1GE	Abcam A-549 MAP3K15 KO 2	Cancer cell line	Male
CVCL_B2NX	Abcam A-549 MAP3K15 KO 1	Cancer cell line	Male

Clinical trials (associated diseases)

203 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,
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge