MAP3K7

Summary

MAP3K7 (mitogen-activated protein kinase kinase kinase 7, HGNC:6859) is a protein-coding gene on chromosome 6q15, encoding Mitogen-activated protein kinase kinase kinase 7 (O43318). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 6885 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiospondylocarpofacial syndrome (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 405 total — 13 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 154
• Druggable target: yes — 29 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_145331

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6859
Approved symbol	MAP3K7
Name	mitogen-activated protein kinase kinase kinase 7
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	MEKK7
Ensembl gene	ENSG00000135341
Ensembl biotype	protein_coding
OMIM	602614
Entrez	6885

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 14 protein_coding, 10 nonsense_mediated_decay, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000369320, ENST00000369325, ENST00000369327, ENST00000369329, ENST00000369332, ENST00000479630, ENST00000700580, ENST00000700581, ENST00000700582, ENST00000700583, ENST00000700584, ENST00000700585, ENST00000700586, ENST00000700587, ENST00000700588, ENST00000700589, ENST00000700590, ENST00000700591, ENST00000700592, ENST00000700593, ENST00000700594, ENST00000703099, ENST00000703100, ENST00000703101, ENST00000871670, ENST00000871671, ENST00000933669, ENST00000933670, ENST00000943036, ENST00000943037

RefSeq mRNA: 4 — MANE Select: NM_145331 NM_003188, NM_145331, NM_145332, NM_145333

CCDS: CCDS5027, CCDS5028, CCDS5029, CCDS5030

Canonical transcript exons

ENST00000369329 — 17 exons

Exon	Start	End
ENSE00000918711	90536337	90536401
ENSE00000918712	90544552	90544632
ENSE00000918714	90547258	90547387
ENSE00000918718	90550468	90550549
ENSE00000918719	90552049	90552179
ENSE00000918721	90553458	90553586
ENSE00000918723	90556500	90556624
ENSE00000918726	90560076	90560214
ENSE00000918728	90561622	90561667
ENSE00000918730	90568558	90568623
ENSE00000918732	90571697	90571807
ENSE00003460863	90518447	90518562
ENSE00003466761	90519258	90519319
ENSE00003566668	90523678	90523783
ENSE00003634556	90548047	90548177
ENSE00003842712	90513579	90516681
ENSE00003844432	90586764	90587072

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 92.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.6583 / max 741.4830, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74747	27.9970	1820
74746	0.6613	277

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	92.38	gold quality
tendon	UBERON:0000043	90.87	gold quality
corpus epididymis	UBERON:0004359	90.55	gold quality
medial globus pallidus	UBERON:0002477	90.30	gold quality
stromal cell of endometrium	CL:0002255	89.86	gold quality
cauda epididymis	UBERON:0004360	89.70	gold quality
caput epididymis	UBERON:0004358	89.56	gold quality
adrenal tissue	UBERON:0018303	89.48	gold quality
ganglionic eminence	UBERON:0004023	89.41	gold quality
corpus callosum	UBERON:0002336	89.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.28	gold quality
calcaneal tendon	UBERON:0003701	89.14	gold quality
ventricular zone	UBERON:0003053	89.06	gold quality
middle temporal gyrus	UBERON:0002771	88.97	gold quality
epithelium of nasopharynx	UBERON:0001951	88.88	gold quality
spleen	UBERON:0002106	88.78	gold quality
tibia	UBERON:0000979	88.58	gold quality
cartilage tissue	UBERON:0002418	88.57	gold quality
endometrium	UBERON:0001295	88.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.45	gold quality
cortical plate	UBERON:0005343	88.40	gold quality
globus pallidus	UBERON:0001875	88.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.06	gold quality
gluteal muscle	UBERON:0002000	87.81	gold quality
adenohypophysis	UBERON:0002196	87.81	gold quality
left ovary	UBERON:0002119	87.74	gold quality
cerebellar hemisphere	UBERON:0002245	87.74	gold quality
monocyte	CL:0000576	87.67	gold quality
cerebellar cortex	UBERON:0002129	87.63	gold quality
mononuclear cell	CL:0000842	87.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NFKB1	Activation

Upstream regulators (CollecTRI, top): E2F4, HR, NFKB

miRNA regulators (miRDB)

134 targeting MAP3K7, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 40)

• Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. (PMID:12242293)
• TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB. (PMID:12296995)
• The TAK1-TAB1 fusion protein is a novel constitutively active mitogen-activated protein kinase kinase kinase that stimulates AP-1 and NF-kappaB signaling pathways (PMID:12372426)
• TNFalpha activation of the NF-kappaB pathway is associated with the inducible binding of TAK1 to TRAF2 and both IKKalpha and IKKbeta (PMID:12547194)
• TAK1- and MKK3-mediated activation of p38 are facilitated by Smad7 (PMID:12589052)
• Pellino2 interacts with TAK1 and activates the MAP kinase pathway. (PMID:12804775)
• TAK1 has a role in TNF-alpha induced IKK phosphorylation of NF-kappaB p65 (PMID:12842894)
• Results indicate that dominant negative constructs of TAK1 retain the ability to intercept the TGF-beta signaling effectively. (PMID:12859960)
• TAB1 participates in a SAPK2a/p38alpha-mediated feedback control of TAK1 (PMID:14592977)
• Tak1 has a role in Wnt signal transduction and phosphorylation and inhibition of TCF (PMID:14960582)
• TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of TAK1 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells (PMID:15125833)
• TAK1 binds with Sef, which has a role in JNK activation and apoptosis (PMID:15277532)
• characterized the molecular mechanisms of cellular stress-induced TAK1 activation, focusing mainly on the phosphorylation of TAK1 at Thr-187 and Ser-192 in the activation loop; TAB1 and TAB2 were differentially involved in the phosphorylation of TAK1 (PMID:15590691)
• Experiments using dominant-negative Tpl2 suggest this kinase functions distal to TRAFs but proximal to the TAK1/TAB1 signaling complex, within the IKK/NFkappaB activation pathway. (PMID:15670770)
• STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases (PMID:15764709)
• interleukin-1beta and its downstream mediator TAK1 inhibit mothers against decapentaplegic homolog 3 MAD-mediated TGFbeta target gene activation (PMID:15917296)
• Arachidonic acid-mediated TAK1 activation is responsible for MAP kinase kinase 6 activation and the ensuing downstream signaling in metastatic human breast carcinoma cells (PMID:16000313)
• Involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway has important implications for understanding of NF-kappaB activation and anhidrotic ectodermal dysplasia in human. (PMID:16251197)
• TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling (PMID:16260783)
• LMP1 utilizes two distinct pathways to activate NF-kappaB: a major one through CTAR2/TRAF6/TAK1/IKKbeta (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKKalpha (noncanonical pathway) (PMID:16280329)
• TAK1 plays a critical role in T cell activation by controlling production of IL-2. (PMID:16293250)
• an LMP1-associated complex containing TRAF6, TAB2, and TAK1 plays an essential role in the activation of JNK (PMID:16446357)
• A candidate gene in ectodermal dysplasia. (PMID:16527194)
• TAK1 is a functional member of the Snf1/AMPK kinase family (PMID:16835226)
• the TAK1-JNK pathway is activated by osmotic stress, while blocking TAK1-mediated NF-kappaB activation; TAO2 regulates TAK1 pathways (PMID:16893890)
• the nuclear factor-kappaB signaling pathway is inhibed by gamma-tocopherol through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis (PMID:17114179)
• The TAB2/TAB3 interaction with TAK1 is crucial for the activation of signaling cascades mediated by interleukin-1, tumor necrosis factor, and receptor activator of nuclear factor-kappa B ligand (RANKL). (PMID:17158449)
• HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation (PMID:17173073)
• HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. (PMID:17202147)
• Modulates TGF-beta-dependent cellular responses by targeting SnoN/SKIL for degradation, thereby allowing the activation of TGF-beta target genes. (PMID:17276978)
• TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells (PMID:17325661)
• Study shows that Tax functions as an intracellular stimulator of an IKK-activating kinase, Tak1; in addition, Tax physically interacts with Tak1 and mediates the recruitment of IKK to Tak1. (PMID:17363973)
• IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2. (PMID:17379600)
• TAK1 as a pivotal upstream kinase and potential therapeutic target to modulate synoviocyte activation in RA. (PMID:17559674)
• BY acting at the level of TAK1 (MAP3K7) activation, YopJ inhibited TLR-mediated NF-kappaB and MAP kinase activation as well as IRF3 signalling. (PMID:17608743)
• p38 negatively regulated TAK1 activity through TAB1 phosphorylation. (PMID:17626013)
• TAK1 contributes to TGF-beta1-mediated tumor angiogenesis and metastasis via involvement of the TAK1-NF-kappaB-MMP-9 pathway. (PMID:17828308)
• These signals exert their anti-inflammatory effects by inhibiting phosphorylation of TAK1 (PMID:17947700)
• two independent and indispensable signaling pathways-1) JAK1-associated PI3K signaling and 2) Act1/TRAF6/TAK1-mediated NF-kappaB activation-are stimulated by IL-17A to regulate gene induction in human airway epithelial cells. (PMID:17982039)
• Data provide insights into the homeostatic interactions that maintain basal NF-kappaB levels by holding the enzymes MEKK3 and TAK1 in their inactive state. (PMID:18206350)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k7	ENSDARG00000020469
mus_musculus	Map3k7	ENSMUSG00000028284
rattus_norvegicus	Map3k7	ENSRNOG00000005724

Paralogs (2): MAP3K7CL (ENSG00000156265), PKDCC (ENSG00000162878)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 7 — O43318 (reviewed: O43318)

Alternative names: Transforming growth factor-beta-activated kinase 1

All UniProt accessions (14): O43318, A0A8V8TPV8, A0A8V8TPW3, A0A8V8TQ28, A0A8V8TQE8, A0A8V8TQF2, A0A8V8TQF4, A0A8V8TQF8, A0A8V8TQL7, A0A8V8TR14, A0A8V8TR17, A0A8V8TRC0, A0A8V8TRC2, A0A8V8TRC6

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs); both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1). Independently of MAP2Ks and p38 MAPKs, acts as a key activator of NF-kappa-B by promoting activation of the I-kappa-B-kinase (IKK) core complex. Mechanistically, recruited to polyubiquitin chains of RIPK2 and IKBKG/NEMO via TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3, and catalyzes phosphorylation and activation of IKBKB/IKKB component of the IKK complex, leading to NF-kappa-B activation. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at ‘Ser-321’ which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis. Phosphorylates STING1 in response to cGAMP-activation, promoting association between STEEP1 and STING1 and STING1 translocation to COPII vesicles.

Subunit / interactions. Can form homodimer. Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3. Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2. Interacts with PPM1L and PPM1B/PP2CB. Interaction with PP2A and PPP6C leads to its repressed activity. Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation. Interacts with DYNC2I2 (via WD domains). Interacts with CYLD and RBCK1. Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6. Interacts with MAPK8IP1 and SMAD6. Interacts with isoform 1 of VRK2. Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation. Interacts with TRIM5. Part of a complex containing ITCH, NDFIP1 and MAP3K7. Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation. Interacts with PLEKHM1 (via N- and C-terminus). Interacts with TRIM8. Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2. Interacts with SASH1. Interacts with RIPK1. (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.

Post-translational modifications. Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation. ‘Lys-48’-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes ‘Lys-48’-linked polyubiquitination catalyzed by ITCH. Requires ‘Lys-63’-linked polyubiquitination for autophosphorylation and subsequent activation. ‘Lys-63’-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves ‘Lys-63’-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP. Deubiquitinated by USP19; leading to negative regulation of TNF- and IL-1beta-triggered NF-kappa-B activation. (Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction. (Microbial infection) Acetylation of Thr-184 and Thr-187 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.

Disease relevance. Frontometaphyseal dysplasia 2 (FMD2) [MIM:617137] A form of frontometaphyseal dysplasia, a progressive sclerosing skeletal dysplasia affecting the long bones and skull. Characteristic features include supraorbital hyperostosis, cranial hyperostosis, undermodeling of the small bones, flared metaphyses, and digital anomalies. Extra-skeletal manifestations include hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. FMD2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Cardiospondylocarpofacial syndrome (CSCF) [MIM:157800] A syndrome characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. CSCF transmission pattern is consistent with autosomal dominant inheritance. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by pro-inflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by ‘Lys-63’-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation. Ceramides are also able to activate MAP3K7/TAK1.

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

Isoforms (4)

UniProt ID	Names	Canonical?
O43318-1	1B	yes
O43318-2	1A
O43318-3	1C
O43318-4	1D

RefSeq proteins (4): NP_003179, NP_663304, NP_663305, NP_663306 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR049637	MAP3K7	Family

Pfam: PF07714

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 (76 total): modified residue 14, helix 14, strand 11, sequence variant 8, compositionally biased region 5, mutagenesis site 5, region of interest 4, turn 4, cross-link 3, splice variant 3, binding site 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
7NTH	X-RAY DIFFRACTION	1.97
7NTI	X-RAY DIFFRACTION	1.98
2EVA	X-RAY DIFFRACTION	2
5JGA	X-RAY DIFFRACTION	2
5V5N	X-RAY DIFFRACTION	2.01
8GW3	X-RAY DIFFRACTION	2.05
5E7R	X-RAY DIFFRACTION	2.11
4GS6	X-RAY DIFFRACTION	2.2
5JH6	X-RAY DIFFRACTION	2.37
5J7S	X-RAY DIFFRACTION	2.37
5JK3	X-RAY DIFFRACTION	2.37
4O91	X-RAY DIFFRACTION	2.39
9FPD	X-RAY DIFFRACTION	2.4
5J8I	X-RAY DIFFRACTION	2.4
2YIY	X-RAY DIFFRACTION	2.49
4L52	X-RAY DIFFRACTION	2.54
4L53	X-RAY DIFFRACTION	2.55
5GJG	X-RAY DIFFRACTION	2.61
4L3P	X-RAY DIFFRACTION	2.68
5J9L	X-RAY DIFFRACTION	2.75
5GJD	X-RAY DIFFRACTION	2.79
5JGB	X-RAY DIFFRACTION	2.8
5GJF	X-RAY DIFFRACTION	2.89
5JGD	X-RAY DIFFRACTION	3.1
9NXF	X-RAY DIFFRACTION	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43318-F1	70.27	0.41

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): 156 (proton acceptor)

Ligand- & substrate-binding residues (2): 42–50; 63

Post-translational modifications (17): 184, 184, 187, 187, 192, 341, 367, 389, 439, 444, 446, 448, 455, 467, 72, 158, 209

Mutagenesis-validated functional residues (5):

Position	Phenotype
34	no effect on ubiquitination.
63	loss of kinase activity. loss of autophosphorylation.
158	abolishes ubiquitination.
209	strongly decreases ubiquitination.
512	enhances autophosphorylation; alters mapk signaling.

Function

Pathways and Gene Ontology

Reactome pathways

62 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-4086398	Ca2+ pathway
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9014325	TICAM1,TRAF6-dependent induction of TAK1 complex
R-HSA-9020702	Interleukin-1 signaling
R-HSA-937042	IRAK2 mediated activation of TAK1 complex
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-HSA-9645460	Alpha-protein kinase 1 signaling pathway
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-1168372	Downstream signaling events of B Cell Receptor (BCR)
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
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

MSigDB gene sets: 903 (showing top): PID_BCR_5PATHWAY, REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, chr6q15, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (58): MAPK cascade (GO:0000165), stimulatory C-type lectin receptor signaling pathway (GO:0002223), positive regulation of T cell cytokine production (GO:0002726), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), inflammatory response (GO:0006954), immune response (GO:0006955), transforming growth factor beta receptor signaling pathway (GO:0007179), canonical NF-kappaB signal transduction (GO:0007249), I-kappaB phosphorylation (GO:0007252), JNK cascade (GO:0007254), negative regulation of gene expression (GO:0010629), positive regulation of macroautophagy (GO:0016239), positive regulation of interleukin-2 production (GO:0032743), toll-like receptor 3 signaling pathway (GO:0034138), toll-like receptor 4 signaling pathway (GO:0034142), TRIF-dependent toll-like receptor signaling pathway (GO:0035666), nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0035872), p38MAPK cascade (GO:0038066), Fc-epsilon receptor signaling pathway (GO:0038095), interleukin-33-mediated signaling pathway (GO:0038172), interleukin-17A-mediated signaling pathway (GO:0038173), defense response to bacterium (GO:0042742), signal transduction in response to DNA damage (GO:0042770), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), anoikis (GO:0043276), positive regulation of JUN kinase activity (GO:0043507), positive regulation of cell cycle (GO:0045787), positive regulation of cell size (GO:0045793), T cell receptor signaling pathway (GO:0050852), stress-activated MAPK cascade (GO:0051403), interleukin-1-mediated signaling pathway (GO:0070498), cellular response to tumor necrosis factor (GO:0071356), cellular response to hypoxia (GO:0071456), positive regulation of cGAS/STING signaling pathway (GO:0141111), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), cellular response to angiotensin (GO:1904385), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), response to hypoxia (GO:0001666)

GO Molecular Function (27): magnesium ion binding (GO:0000287), transcription coactivator binding (GO:0001223), protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), MAP kinase kinase kinase activity (GO:0004709), type II transforming growth factor beta receptor binding (GO:0005114), ATP binding (GO:0005524), MAP kinase kinase kinase kinase activity (GO:0008349), kinase activity (GO:0016301), receptor tyrosine kinase binding (GO:0030971), ubiquitin protein ligase binding (GO:0031625), histone kinase activity (GO:0035173), identical protein binding (GO:0042802), scaffold protein binding (GO:0097110), protein serine kinase activity (GO:0106310), protein serine/threonine kinase binding (GO:0120283), DNA-binding transcription factor binding (GO:0140297), linear polyubiquitin binding (GO:1990450), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), signaling receptor binding (GO:0005102), protein binding (GO:0005515), transferase activity (GO:0016740), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), ATAC complex (GO:0140672), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2
Toll Like Receptor 3 (TLR3) Cascade	2
TRIF (TICAM1)-mediated TLR4 signaling	2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	2
MyD88 cascade initiated on plasma membrane	2
MAP kinase activation	2
Downstream signaling events of B Cell Receptor (BCR)	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
TCR signaling	1
Fc epsilon receptor (FCERI) signaling	1
Beta-catenin independent WNT signaling	1
Interleukin-1 signaling	1
TNF signaling	1
C-type lectin receptors (CLRs)	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	5
protein kinase activity	3
protein serine/threonine kinase activity	3
cellular anatomical structure	3
intracellular signaling cassette	2
positive regulation of cytokine production	2
protein binding	2
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
T cell cytokine production	1
positive regulation of T cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of T cell cytokine production	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
toll-like receptor signaling pathway	1
defense response	1
immune system process	1
response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
protein phosphorylation	1
canonical NF-kappaB signal transduction	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
interleukin-2 production	1
regulation of interleukin-2 production	1
endolysosomal toll-like receptor signaling pathway	1
cell surface toll-like receptor signaling pathway	1
MyD88-independent toll-like receptor signaling pathway	1
cytoplasmic pattern recognition receptor signaling pathway	1
Fc receptor signaling pathway	1
metal ion binding	1
transcription coregulator binding	1
transforming growth factor beta receptor binding	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

4434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K7	TAB1	Q15750	998
MAP3K7	TAB2	Q9NYJ8	998
MAP3K7	TRAF6	Q9Y4K3	997
MAP3K7	TAB3	Q8N5C8	995
MAP3K7	MYD88	P78397	965
MAP3K7	IKBKG	Q9Y6K9	928
MAP3K7	RIPK1	Q13546	883
MAP3K7	TNF	P01375	787
MAP3K7	G3V2F7	G3V2F7	773
MAP3K7	TRADD	Q15628	768
MAP3K7	JUN	P05412	742
MAP3K7	CASP8	Q14790	731
MAP3K7	XIAP	P98170	731
MAP3K7	UBE2N	P61088	710
MAP3K7	TRAF3	Q13114	687

IntAct

188 interactions, top by confidence:

A	B	Type	Score
MAP3K7	TAB2	psi-mi:“MI:0915”(physical association)	0.920
TAB2	MAP3K7	psi-mi:“MI:0914”(association)	0.920
MAP3K7	TAB1	psi-mi:“MI:0915”(physical association)	0.900
MAP3K7	TAB1	psi-mi:“MI:0914”(association)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
TAB1	MAP3K7	psi-mi:“MI:0914”(association)	0.900
MAP3K7	TAB1	psi-mi:“MI:2364”(proximity)	0.900
TAB1	MAP3K7	psi-mi:“MI:0915”(physical association)	0.900
TAB3	MAP3K7	psi-mi:“MI:0914”(association)	0.830
TAB3	MAP3K7	psi-mi:“MI:0915”(physical association)	0.830
MAP3K7	UBC	psi-mi:“MI:0915”(physical association)	0.740
UBC	MAP3K7	psi-mi:“MI:0915”(physical association)	0.740
MAP3K7	MAPK8IP1	psi-mi:“MI:0915”(physical association)	0.720
MAPK8IP1	MAP3K7	psi-mi:“MI:0914”(association)	0.720

BioGRID (835): MAP3K7 (Reconstituted Complex), NFKBIA (Biochemical Activity), MAP3K7 (Affinity Capture-Western), ECSIT (Affinity Capture-Western), MAP3K7 (Affinity Capture-MS), MAP3K7 (Affinity Capture-MS), MAP3K7 (Affinity Capture-MS), MAP3K7 (Affinity Capture-MS), vpr (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), TAB1 (Affinity Capture-Western), TAB2 (Affinity Capture-Western), TAB3 (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), MAP3K14 (Affinity Capture-Western)

ESM2 similar proteins: A2VDU3, A7E3S4, A8XJW8, E9PUQ8, F1QGZ6, O35346, O43318, O54748, P04049, P05625, P09560, P0C8E4, P11345, P11346, P27966, P33886, P34152, P34908, P42331, Q00944, Q04982, Q05397, Q07192, Q07292, Q08BR4, Q16760, Q21029, Q3UVC0, Q56R14, Q5R5M7, Q5RFL3, Q5U2Z7, Q61083, Q61084, Q61097, Q61UC4, Q62073, Q69Z98, Q6GPK9, Q6VAB6

Diamond homologs: A0A2R6XIK6, A2VDU3, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, F4JTP5, G5EE56, O01700, O22558, O35346, O43283, O43318, O64768, P08630, P0C8E4, P0CD62, P18106, P18160, P18161, P29317, P32577, P34152, P41239, P41240, P41241, P42680, P42686, P42690, P51813, P80192, P97504, Q00944, Q02779, Q02977, Q03145, Q05397, Q05609, Q0VBZ0

SIGNOR signaling

75 interactions.

A	Effect	B	Mechanism
TAB2	“up-regulates activity”	MAP3K7	binding
MAP3K7	“up-regulates activity”	IKBKB	phosphorylation
MAP3K7	“up-regulates activity”	MAP2K6	phosphorylation
MAP3K7	down-regulates	KSR1	phosphorylation
TAB3	“up-regulates activity”	MAP3K7	binding
MAP3K7	down-regulates	HDAC7	phosphorylation
PPP2CA	down-regulates	MAP3K7	dephosphorylation
PPP6C	down-regulates	MAP3K7	dephosphorylation
TAB1	“up-regulates activity”	MAP3K7	binding
MAP3K7	“up-regulates activity”	IKBKG	binding
TRAF2	“up-regulates activity”	MAP3K7	ubiquitination
MAP3K7	“up-regulates activity”	IKK-complex	phosphorylation
MAP3K7	up-regulates	IKK-complex	phosphorylation
MAP3K7	“up-regulates activity”	MAP3K7	phosphorylation
TRAF6	“up-regulates activity”	MAP3K7	ubiquitination
MAP3K7	“up-regulates activity”	MAP2K3	phosphorylation
PPP6C	“down-regulates activity”	MAP3K7	dephosphorylation
RIPK1	“up-regulates activity”	MAP3K7	binding
MAP3K7	“down-regulates quantity by destabilization”	TNFAIP8L2	phosphorylation
MAP3K7	“up-regulates activity”	MAP2K7	phosphorylation
MAP3K7	“up-regulates activity”	TAB1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	5	37.0×	6e-06
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	7	35.3×	7e-08
TRAF6-mediated induction of TAK1 complex within TLR4 complex	5	34.6×	8e-06
Regulation of NF-kappa B signaling	5	30.8×	2e-05
TNFR1-induced NF-kappa-B signaling pathway	9	29.4×	3e-09
TICAM1, RIP1-mediated IKK complex recruitment	5	29.2×	2e-05
activated TAK1 mediates p38 MAPK activation	6	28.9×	3e-06
TAK1-dependent IKK and NF-kappa-B activation	9	26.3×	6e-09

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	6	37.7×	5e-06
canonical NF-kappaB signal transduction	7	19.1×	3e-05
tumor necrosis factor-mediated signaling pathway	6	14.8×	8e-04
positive regulation of miRNA transcription	6	13.0×	1e-03
receptor internalization	5	12.1×	7e-03
positive regulation of interleukin-1 beta production	6	11.6×	2e-03
obsolete positive regulation of NF-kappaB transcription factor activity	7	10.7×	9e-04
negative regulation of canonical NF-kappaB signal transduction	8	10.3×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	12
Uncertain significance	181
Likely benign	111
Benign	45

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1341502	NM_145331.3(MAP3K7):c.616T>G (p.Tyr206Asp)	Pathogenic
2034147	NM_145331.3(MAP3K7):c.328G>A (p.Gly110Ser)	Pathogenic
264698	NM_145331.3(MAP3K7):c.1535C>T (p.Pro512Leu)	Pathogenic
264699	NM_145331.3(MAP3K7):c.208G>C (p.Glu70Gln)	Pathogenic
264700	NM_145331.3(MAP3K7):c.299T>A (p.Val100Glu)	Pathogenic
264701	NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg)	Pathogenic
264702	NM_145331.3(MAP3K7):c.130_135del (p.Arg44_Gly45del)	Pathogenic
264704	NM_145331.3(MAP3K7):c.145GTT[1] (p.Val50del)	Pathogenic
264705	NM_145331.3(MAP3K7):c.721T>A (p.Trp241Arg)	Pathogenic
4075719	NM_145331.3(MAP3K7):c.560C>T (p.Thr187Ile)	Pathogenic
423266	NM_145331.3(MAP3K7):c.721T>G (p.Trp241Gly)	Pathogenic
4292241	NM_145331.3(MAP3K7):c.329G>A (p.Gly110Asp)	Pathogenic
974910	NM_145331.3(MAP3K7):c.737-7A>G	Pathogenic
1173089	NM_145331.3(MAP3K7):c.815C>A (p.Ser272Tyr)	Likely pathogenic
1349311	NM_145331.3(MAP3K7):c.625_627dup (p.Lys209dup)	Likely pathogenic
264703	NM_145331.3(MAP3K7):c.328G>T (p.Gly110Cys)	Likely pathogenic
3337266	NM_145331.3(MAP3K7):c.317A>G (p.Tyr106Cys)	Likely pathogenic
3372549	NM_145331.3(MAP3K7):c.467A>T (p.Asp156Val)	Likely pathogenic
372406	NM_145331.3(MAP3K7):c.521G>A (p.Cys174Tyr)	Likely pathogenic
422420	NM_145331.3(MAP3K7):c.319G>A (p.Ala107Thr)	Likely pathogenic
452368	NM_145331.3(MAP3K7):c.617A>G (p.Tyr206Cys)	Likely pathogenic
4819273	NM_145331.3(MAP3K7):c.575G>A (p.Ser192Asn)	Likely pathogenic
639687	NM_145331.3(MAP3K7):c.230A>C (p.Glu77Ala)	Likely pathogenic
684731	NM_145331.3(MAP3K7):c.122TTG[1] (p.Val42del)	Likely pathogenic
801006	NM_145331.3(MAP3K7):c.608-1G>A	Likely pathogenic

SpliceAI

3307 predictions. Top by Δscore:

Variant	Effect	Δscore
6:90516677:CTTGC:C	acceptor_gain	1.0000
6:90516680:GCCTA:G	acceptor_loss	1.0000
6:90516682:C:CC	acceptor_gain	1.0000
6:90518440:AACTT:A	donor_loss	1.0000
6:90518441:ACTT:A	donor_loss	1.0000
6:90518442:CTTAC:C	donor_loss	1.0000
6:90518443:TTA:T	donor_loss	1.0000
6:90518444:TA:T	donor_loss	1.0000
6:90518445:A:AC	donor_gain	1.0000
6:90518445:AC:A	donor_loss	1.0000
6:90518445:ACTTT:A	donor_gain	1.0000
6:90518446:C:CT	donor_gain	1.0000
6:90518446:CT:C	donor_gain	1.0000
6:90518446:CTT:C	donor_gain	1.0000
6:90518446:CTTT:C	donor_gain	1.0000
6:90518446:CTTTC:C	donor_gain	1.0000
6:90518449:T:A	donor_gain	1.0000
6:90518559:GAGG:G	acceptor_gain	1.0000
6:90518561:GG:G	acceptor_gain	1.0000
6:90518563:C:CC	acceptor_gain	1.0000
6:90518563:CTGAA:C	acceptor_loss	1.0000
6:90518575:A:T	acceptor_gain	1.0000
6:90519253:TTTA:T	donor_loss	1.0000
6:90519254:TTAC:T	donor_loss	1.0000
6:90519255:TACCT:T	donor_loss	1.0000
6:90519256:ACCTG:A	donor_loss	1.0000
6:90519257:C:A	donor_loss	1.0000
6:90520054:CAA:C	donor_gain	1.0000
6:90536331:TCTTA:T	donor_loss	1.0000
6:90536332:CTTA:C	donor_loss	1.0000

AlphaMissense

3988 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:90516547:A:G	L592P	1.000
6:90516580:A:G	L581P	1.000
6:90516601:A:G	L574P	1.000
6:90516622:A:G	L567P	1.000
6:90516661:A:G	L554P	1.000
6:90516673:A:G	L550P	1.000
6:90518466:C:G	A541P	1.000
6:90518477:T:G	Q537P	1.000
6:90518490:A:C	Y533D	1.000
6:90518498:G:T	A530E	1.000
6:90518499:C:G	A530P	1.000
6:90518510:T:C	H526R	1.000
6:90518510:T:G	H526P	1.000
6:90518511:G:C	H526D	1.000
6:90518518:A:C	F523L	1.000
6:90518518:A:T	F523L	1.000
6:90518520:A:G	F523L	1.000
6:90518520:A:T	F523I	1.000
6:90518531:G:A	S519F	1.000
6:90518532:A:G	S519P	1.000
6:90518552:G:T	P512Q	1.000
6:90518561:G:C	P509R	1.000
6:90518561:G:T	P509H	1.000
6:90518562:G:A	P509S	1.000
6:90518562:G:T	P509T	1.000
6:90519262:A:G	L507P	1.000
6:90519274:A:G	L503P	1.000
6:90552092:G:T	P275H	1.000
6:90552093:G:A	P275S	1.000
6:90552096:G:T	R274S	1.000

dbSNP variants (sampled 300 via entrez): RS1000074322 (6:90568459 TAAAA>T,TAAA,TAAAAA,TAAAAAAAAAAAA), RS1000100158 (6:90559316 C>G,T), RS1000116004 (6:90548694 C>T), RS1000187304 (6:90538986 T>C), RS1000260237 (6:90584879 T>A), RS1000384124 (6:90552905 G>C), RS1000547796 (6:90526091 C>A,T), RS1000589629 (6:90540523 G>A), RS1000614971 (6:90551048 C>T), RS1000618710 (6:90572686 T>G), RS1000792831 (6:90516990 G>C), RS1000848268 (6:90573235 T>C), RS1000965264 (6:90564592 G>A,C), RS1000969113 (6:90579453 T>C), RS1001058977 (6:90566954 A>C,G)

Disease associations

OMIM: gene MIM:602614 | disease phenotypes: MIM:157800, MIM:617137

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiospondylocarpofacial syndrome	Strong	Autosomal dominant
frontometaphyseal dysplasia 2	Strong	Autosomal dominant
frontometaphyseal dysplasia	Strong	Autosomal dominant

Mondo (3): cardiospondylocarpofacial syndrome (MONDO:0008005), frontometaphyseal dysplasia 2 (MONDO:0014935), frontometaphyseal dysplasia (MONDO:0015942)

Orphanet (1): Cardiospondylocarpofacial syndrome (Orphanet:3238)

HPO phenotypes

154 total (30 of 154 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000201	Pierre-Robin sequence
HP:0000218	High palate
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000612_23	Celiac disease	4.000000e-10
GCST001200_8	Graves’ disease	2.000000e-06
GCST002337_11	Amyotrophic lateral sclerosis (sporadic)	5.000000e-07
GCST002432_7	Response to inhaled corticosteroid treatment in asthma (change in FEV1)	7.000000e-06
GCST003329_1	Response to anti-TNF therapy in rheumatoid arthritis	7.000000e-07
GCST003329_4	Response to anti-TNF therapy in rheumatoid arthritis	3.000000e-08
GCST005212_30	Asthma	2.000000e-12
GCST005929_4	Severity of nausea and vomiting of pregnancy	3.000000e-10
GCST006444_13	Bone mineral density (hip)	4.000000e-06
GCST006862_5	Asthma	9.000000e-13
GCST007993_14	Asthma (adult onset)	6.000000e-12
GCST007995_49	Asthma (childhood onset)	9.000000e-10
GCST009798_19	Asthma	5.000000e-27
GCST011616_17	Cortical volume	5.000000e-10
GCST011617_9	Cortical surface area	1.000000e-23

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement
EFO:0004653	response to TNF antagonist
EFO:0009265	nausea and vomiting of pregnancy severity measurement
EFO:0007702	hip bone mineral density
EFO:1002011	adult onset asthma

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538064	Frontometaphyseal dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3038499 (PROTEIN COMPLEX), CHEMBL5776 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

29 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 787,687 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL477	ADENOSINE	4	222,014
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL14249	ADENOSINE TRIPHOSPHATE	2	287,353
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2
CHEMBL215152	DEFOSBARASERTIB	2
CHEMBL230011	TG100-115	2
CHEMBL475251	R-406	2
CHEMBL558752	RAF-265	2
CHEMBL572878	TOZASERTIB	2
CHEMBL1908397	KW-2449	1
CHEMBL296468	BMS-387032	1
CHEMBL574738	AST-487	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — TAK1 subfamily

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
compound 25 [PMID: 28038940]	Inhibition	8.62	pIC50
RGB-286638	Inhibition	8.3	pIC50
5Z-7-oxozeaenol	Inhibition	8.05	pIC50
Takinib	Inhibition	8.02	pIC50
compound 12 [PMID: 27448772]	Inhibition	7.96	pIC50
compound 17d [PMID: 23099093]	Inhibition	7.92	pIC50
CEP-11981	Inhibition	7.85	pIC50
compound 5 [PMID: 28038940]	Inhibition	7.3	pIC50
NG-25	Inhibition	6.83	pIC50

Binding affinities (BindingDB)

50 measured of 56 human assays (56 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(E)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	3.1 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-(4-butan-2-yloxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enamide	IC50	4.3 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-(4-propan-2-yloxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enamide	IC50	4.4 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(2,2-dimethylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	5.2 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-ynamide	IC50	7 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
(4S,6E,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	IC50	11 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-3-[4-[(2-methylpropan-2-yl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	13 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(4,4-difluorocyclohexyl)oxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	16 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
N-[3-[2-[4-amino-1-(1-methylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	18 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
(E)-3-(4-propoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enamide	IC50	19 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(2,2,2-trifluoroethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	33 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
CHEBI:83275	IC50	33 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-N-methyl-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	41 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-[(3-fluorophenyl)methoxy]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	51 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(2-hydroxy-2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	75 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(4S,6Z,9S,10S,12E)-15,15-difluoro-9,10-dihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,16-tetraene-2,8,18-trione	IC50	77 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-N,N-dimethyl-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	97 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-4-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]but-3-en-2-one	IC50	100 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(Z)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enenitrile	IC50	170 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enamide	IC50	170 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-N-cyclopropyl-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	180 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-1-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]pent-1-en-3-one	IC50	200 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
methyl (E)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enoate	IC50	200 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enenitrile	IC50	210 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
2-chloro-1-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]ethanone	IC50	280 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-(4-phenylmethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enenitrile	IC50	330 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enoic acid	IC50	340 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-N-ethyl-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	340 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
methyl (E)-3-(4-phenylmethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enoate	IC50	350 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(Z)-2-chloro-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	360 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(4S,6Z,9S,10S,12E)-15-bromo-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	IC50	360 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-N-(cyclopropylmethyl)-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	380 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(2E,5S,9S,11Z,14S)-18-hydroxy-20-methoxy-7,7,14-trimethyl-6,8,15-trioxatricyclo[15.4.0.05,9]henicosa-1(17),2,11,18,20-pentaene-10,16-dione	IC50	380 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-4-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]but-2-enamide	IC50	420 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
methyl (E)-2-methyl-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enoate	IC50	430 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile	IC50	560 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-3-(4-phenylmethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-enamide	IC50	730 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
2-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enenitrile	IC50	750 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(Z)-2-fluoro-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	860 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(2S,4S,6S,7S,9Z,12S)-6,7,16-trihydroxy-18-methoxy-12-methyl-3,13-dioxatricyclo[13.4.0.02,4]nonadeca-1(15),9,16,18-tetraene-8,14-dione	IC50	990 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
CHEBI:67558	IC50	1300 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(E)-N-[(2S)-2-hydroxypropyl]-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	1600 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
1-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]ethanone	IC50	1700 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(E)-N-[(2R)-2-hydroxypropyl]-3-[4-(2-methylpropoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]prop-2-enamide	IC50	2500 nM	US-9505765: 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds as TAK1 inhibitors in disease treatment
(4S,6Z,9S,10S,12E)-17-bromo-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(18),6,12,14,16-pentaene-2,8-dione	IC50	2600 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(4S,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),12,15,17-tetraene-2,8-dione	IC50	2600 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
(4S,6Z,9S,10S,12E)-15,17-dibromo-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	IC50	8900 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
ZEAENOL	IC50	10000 nM	US-10434085: Non-aromatic difluoro analogues of resorcylic acid lactones
CHEMBL3823800	IC50	20000 nM

ChEMBL bioactivities

517 potent at pChembl≥5 of 536 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.90	IC50	1.259	nM	CHEMBL6148246
8.82	Kd	1.5	nM	AST-487
8.80	IC50	1.585	nM	CHEMBL6151387
8.77	IC50	1.7	nM	CHEMBL3885421
8.70	IC50	2	nM	CHEMBL4796239
8.70	IC50	1.995	nM	CHEMBL6149378
8.64	IC50	2.3	nM	CHEMBL3823127
8.62	IC50	2.4	nM	CHEMBL3884839
8.60	IC50	2.512	nM	CHEMBL6152193
8.60	IC50	2.512	nM	CHEMBL6147547
8.54	Kd	2.9	nM	LESTAURTINIB
8.52	IC50	3	nM	CHEMBL3823992
8.51	IC50	3.1	nM	CHEMBL3953067
8.50	IC50	3.162	nM	CHEMBL6102341
8.49	IC50	3.2	nM	CHEMBL3884616
8.48	IC50	3.3	nM	CHEMBL3884569
8.46	IC50	3.5	nM	CHEMBL3823882
8.40	IC50	4	nM	CHEMBL2407759
8.40	IC50	3.981	nM	CHEMBL6149879
8.40	IC50	3.981	nM	CHEMBL6142895
8.40	IC50	3.981	nM	CHEMBL6152193
8.39	Kd	4.1	nM	NINTEDANIB
8.37	IC50	4.3	nM	CHEMBL3916326
8.36	IC50	4.4	nM	CHEMBL3884229
8.36	IC50	4.4	nM	CHEMBL3924740
8.34	IC50	4.6	nM	CHEMBL3884281
8.30	IC50	5	nM	CHEMBL3822845
8.30	IC50	5	nM	CHEMBL4752978
8.30	IC50	5.012	nM	CHEMBL6133079
8.30	IC50	5.012	nM	CHEMBL6149378
8.30	IC50	5.012	nM	CHEMBL6148246
8.29	IC50	5.1	nM	CHEMBL3884960
8.28	IC50	5.2	nM	CHEMBL3822712
8.28	IC50	5.2	nM	CHEMBL3919781
8.25	IC50	5.6	nM	CHEMBL1077979
8.24	IC50	5.8	nM	CHEMBL3823000
8.20	IC50	6.3	nM	REBASTINIB
8.20	IC50	6.31	nM	CHEMBL6143169
8.20	IC50	6.31	nM	CHEMBL6101930
8.17	IC50	6.7	nM	CHEMBL3822889
8.15	IC50	7	nM	CHEMBL3884642
8.15	IC50	7	nM	CHEMBL3917140
8.14	IC50	7.3	nM	CHEMBL3823892
8.14	IC50	7.3	nM	CHEMBL3884143
8.14	Kd	7.2	nM	CHEMBL1908395
8.12	IC50	7.6	nM	CHEMBL3884839
8.10	IC50	8	nM	CHEMBL3823303
8.10	IC50	8	nM	CHEMBL5076447
8.10	IC50	7.943	nM	CHEMBL6148701
8.10	IC50	7.943	nM	CHEMBL6101930

PubChem BioAssay actives

411 with measured affinity, of 1347 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
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624724: Binding constant for TAK1 kinase domain	kd	0.0015	uM
[2-[[2-[3-(4-acetylpiperazin-1-yl)anilino]-5-chloropyrimidin-4-yl]amino]phenyl] prop-2-enoate	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0017	uM
2-[5-[[2-(difluoromethoxy)phenyl]methyl-[(2R)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-1H-imidazole-2-carbonyl]-1,3-dihydroisoindole-5-carboxamide	1709608: Inhibition of recombinant human full-length His-tagged TAK1-TAB1 fusion protein (437 to 504 residues) expressed in baculovirus expression system using fluorescein-MAP2K1 as substrate preincubated for 30 mins followed by substrate addition and measured after 60 mins in presence of ATP by lanthascreen TR-FRET assay	ic50	0.0020	uM
N-[4-(4-methylpiperazine-1-carbonyl)-2-phenylphenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0023	uM
N-[2-[5-chloro-2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0024	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	508100: Binding affinity to TAK1	kd	0.0029	uM
N-[2-(1-fluoroethoxy)-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0030	uM
[2-[[5-chloro-2-(3-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl] prop-2-enoate	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0032	uM
[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl] prop-2-enoate	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0033	uM
N-[4-(4-methylpiperazine-1-carbonyl)-2-propan-2-ylphenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0035	uM
1-[4-[4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]piperidin-1-yl]ethanone	762666: Inhibition of truncated TAK1-TAB1(unknown origin) using MKK7 as substrate by ALPHAScreen assay in presence of ATP	ic50	0.0040	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624724: Binding constant for TAK1 kinase domain	kd	0.0041	uM
[2-[[5-chloro-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl] prop-2-enoate	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0044	uM
N-[2-[5-chloro-2-[[1-(oxan-4-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0046	uM
N-[2-(dimethylamino)-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0050	uM
2-[5-[[2-(difluoromethoxy)phenyl]methyl-[2-(methylamino)-2-oxoethyl]carbamoyl]-1H-imidazole-2-carbonyl]-1,3-dihydroisoindole-5-carboxamide	1709608: Inhibition of recombinant human full-length His-tagged TAK1-TAB1 fusion protein (437 to 504 residues) expressed in baculovirus expression system using fluorescein-MAP2K1 as substrate preincubated for 30 mins followed by substrate addition and measured after 60 mins in presence of ATP by lanthascreen TR-FRET assay	ic50	0.0050	uM
N-[2-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0051	uM
N-[2-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0052	uM
(4S,6Z,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0056	uM
N-[2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0058	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168193: Inhibition of human wild type TAK1 using RB-S6P as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.0063	uM
N-[2-cyclohexyl-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0067	uM
N-[2-[5-chloro-2-[[1-(difluoromethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0070	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624724: Binding constant for TAK1 kinase domain	kd	0.0072	uM
N-[2-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0073	uM
N-[2-bromo-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0073	uM
(1S,2S,3R,4R)-3-[[5-methyl-2-[3-(pyrrolidine-1-carbonyl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1815955: Inhibition of TAK1 (unknown origin) in presence of MBP as substrate by ADP-Glo assay	ic50	0.0080	uM
1-[2-[3-ethyl-5-[(5-fluoro-4-imidazo[1,2-b]pyridazin-3-ylpyrimidin-2-yl)amino]phenoxy]ethyl]piperidin-4-ol	1311912: Inhibition of recombinant FLAG-tagged TAK1 kinase domain (unknown origin) expressed in baculovirus expression system coexpressing TAB using biotin-labeled MKK6kd substrate incubated for 1 hr by AlphaScreen assay	ic50	0.0080	uM
(2Z)-2-[(Z)-(5-bromo-2-oxo-1H-indol-3-ylidene)hydrazinylidene]-3-(4-hydroxyphenyl)-1,3-thiazolidin-4-one	589426: Competitive inhibition of recombinant TAK1-TAB1 assessed as [33P]gamma-ATP incorporation into substrate histone H1 peptide by filter plate assay	ic50	0.0089	uM
4-[4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]cyclohexan-1-ol	762866: Inhibition of TAK1-TAB1 (unknown origin) by alphascreen assay in presence of ATP	ic50	0.0090	uM
N-[2-[ethyl(methyl)amino]-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0093	uM
1-[4-[4-[7-amino-2-(1,3-benzothiazol-7-yl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]piperidin-1-yl]ethanone	762665: Inhibition of TAK1 in human HCT116 cells assessed as inhibition of TNF-alpha-stimulated JNK phosphorylation	ic50	0.0100	uM
4-[4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-chlorofuro[2,3-c]pyridin-4-yl]pyrazol-1-yl]cyclohexan-1-ol	1709608: Inhibition of recombinant human full-length His-tagged TAK1-TAB1 fusion protein (437 to 504 residues) expressed in baculovirus expression system using fluorescein-MAP2K1 as substrate preincubated for 30 mins followed by substrate addition and measured after 60 mins in presence of ATP by lanthascreen TR-FRET assay	ic50	0.0100	uM
(1S,2S,3R,4R)-3-[[5-(furan-3-yl)-2-[3-(pyrrolidine-1-carbonyl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1815955: Inhibition of TAK1 (unknown origin) in presence of MBP as substrate by ADP-Glo assay	ic50	0.0110	uM
(1S,2S,3R,4R)-3-[[5-cyclopropyl-2-[3-(pyrrolidine-1-carbonyl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1815955: Inhibition of TAK1 (unknown origin) in presence of MBP as substrate by ADP-Glo assay	ic50	0.0110	uM
N-[3-(4-methylpiperazine-1-carbonyl)-2-propan-2-yloxyphenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0110	uM
1-[5-(4-methylpiperazin-1-yl)naphthalen-2-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]urea	1436866: Binding affinity to recombinant human biotinylated N-terminal GST-tagged autophosphorylated TAK1 (1 to 303 residues) fused with TAB1 (437 to 504 residues) expressed in baculovirus infected sf9 cells by SPR assay	kd	0.0120	uM
N-[2-methoxy-4-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0130	uM
4-[4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-(difluoromethyl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]cyclohexan-1-ol	762866: Inhibition of TAK1-TAB1 (unknown origin) by alphascreen assay in presence of ATP	ic50	0.0140	uM
N-[1-(4-hydroxycyclohexyl)-5-(piperidin-1-ylmethyl)benzimidazol-2-yl]-3-nitrobenzamide	1262278: Inhibition of TAK1 (unknown origin)	ki	0.0150	uM
N-[2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl]-4-oxo-3H-thieno[3,2-d]pyrimidine-7-carboxamide	1311892: Inhibition of GST-tagged TAK1 (unknown origin) expressed in sf9 cells coexpressing His-tagged TAB1 using myelin basic protein as substrate incubated for 30 mins in presence of [33P]ATP by microbeta scintillation counting method	ic50	0.0150	uM
(1S,2S,3R,4R)-3-[[5-(2-fluoro-4-pyridinyl)-2-[3-(pyrrolidine-1-carbonyl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1815955: Inhibition of TAK1 (unknown origin) in presence of MBP as substrate by ADP-Glo assay	ic50	0.0170	uM
7-amino-2-(1,2,3-benzothiadiazol-7-yl)-4-[1-(4-hydroxycyclohexyl)pyrazol-4-yl]furo[2,3-c]pyridine-3-carbonitrile	762864: Inhibition of TAK1 in human HCT116 cells assessed as inhibition of TNF-alpha-stimulated JNK phosphorylation	ic50	0.0170	uM
4-[4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-(fluoromethyl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]cyclohexan-1-ol	762866: Inhibition of TAK1-TAB1 (unknown origin) by alphascreen assay in presence of ATP	ic50	0.0170	uM
1-[4-[4-[7-amino-2-(1-methylpyrrolo[2,3-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]piperidin-1-yl]ethanone	762666: Inhibition of truncated TAK1-TAB1(unknown origin) using MKK7 as substrate by ALPHAScreen assay in presence of ATP	ic50	0.0180	uM
(2Z)-2-[(Z)-(5-chloro-2-oxo-1H-indol-3-ylidene)hydrazinylidene]-3-(4-hydroxyphenyl)-1,3-thiazolidin-4-one	589426: Competitive inhibition of recombinant TAK1-TAB1 assessed as [33P]gamma-ATP incorporation into substrate histone H1 peptide by filter plate assay	ic50	0.0210	uM
1-[4-[4-[7-amino-2-(1,2-benzothiazol-7-yl)furo[2,3-c]pyridin-4-yl]pyrazol-1-yl]piperidin-1-yl]ethanone	762666: Inhibition of truncated TAK1-TAB1(unknown origin) using MKK7 as substrate by ALPHAScreen assay in presence of ATP	ic50	0.0230	uM
(1S,2S,3R,4R)-3-[[5-(2-fluorophenyl)-2-[3-(pyrrolidine-1-carbonyl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1815955: Inhibition of TAK1 (unknown origin) in presence of MBP as substrate by ADP-Glo assay	ic50	0.0240	uM
2-chloro-N-[2-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]acetamide	1336652: Inhibition of full length recombinant human GST-tagged TAK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0250	uM
2-chloro-N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]acetamide	1490296: Inhibition of TAK1 (unknown origin) by LanthaScreen assay	ic50	0.0250	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
takinib	affects binding, decreases activity, decreases phosphorylation	2
sodium arsenite	increases expression	2
7-oxozeanol	decreases reaction, increases activity, increases phosphorylation, decreases activity	2
Methotrexate	decreases expression, increases phosphorylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
Antirheumatic Agents	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
moringin	decreases expression	1
TAK1 inhibitor NG25	decreases activity	1
2-anisidine	decreases expression	1
triphenyl phosphate	affects expression	1
kaempferol	decreases reaction, increases phosphorylation	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
methylparaben	increases expression	1
manganese chloride	increases methylation	1
coumarin	affects phosphorylation	1
casticin	increases expression	1
capsazepine	decreases reaction, increases activity, increases phosphorylation	1
anacardic acid	decreases activity	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
1,1-dimethylbutyl-1-deoxy-Delta(9)-THC	increases phosphorylation, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
asparanin A	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	affects response to substance, decreases expression, increases abundance, increases expression	1

ChEMBL screening assays

375 unique, capped per target: 374 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1105931	Binding	Inhibition of TAK1/TAB1 at 5 uM	Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. — Bioorg Med Chem Lett
CHEMBL4625643	ADMET	Inhibition of human wild type partial length TAK1 (1 to 303 residues) expressed in mammalian expression system	Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis. — ACS Med Chem Lett

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 2 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3AL	Abcam HEK293T MAP3K7 KO	Transformed cell line	Female
CVCL_B7EZ	UNIBSi017-A	Induced pluripotent stem cell	Female
CVCL_B8K3	Abcam HCT 116 MAP3K7 KO	Cancer cell line	Male
CVCL_B8YK	Abcam MCF-7 MAP3K7 KO	Cancer cell line	Female
CVCL_B9MB	Abcam A-549 MAP3K7 KO	Cancer cell line	Male
CVCL_D7UD	Ubigene A-549 MAP3K7 KO	Cancer cell line	Male
CVCL_D8Q4	Ubigene HCT 116 MAP3K7 KO	Cancer cell line	Male
CVCL_D9JG	Ubigene HEK293 MAP3K7 KO	Transformed cell line	Female
CVCL_E0HB	Ubigene HeLa MAP3K7 KO	Cancer cell line	Female
CVCL_SW73	HAP1 MAP3K7 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05857085	PHASE4	COMPLETED	Novel Therapeutics and Endothelial Dysfunction in T1DM Patients
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT01862146	Not specified	COMPLETED	Arterial Remodeling in Smokers
NCT02127333	Not specified	COMPLETED	Role of Oxygen for Vascular Dysfunction
NCT04199949	Not specified	COMPLETED	Effects of Five Days of Physical Inactivity on Endothelial Function in Healthy Humans