MAP3K5

Summary

MAP3K5 (mitogen-activated protein kinase kinase kinase 5, HGNC:6857) is a protein-coding gene on chromosome 6q23.3, encoding Mitogen-activated protein kinase kinase kinase 5 (Q99683). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK.

Source: NCBI Gene 4217 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 152 total
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6857
Approved symbol	MAP3K5
Name	mitogen-activated protein kinase kinase kinase 5
Location	6q23.3
Locus type	gene with protein product
Status	Approved
Aliases	MAPKKK5, ASK1
Ensembl gene	ENSG00000197442
Ensembl biotype	protein_coding
OMIM	602448
Entrez	4217

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000359015, ENST00000463140, ENST00000698928, ENST00000903035, ENST00000903036, ENST00000903037, ENST00000903038, ENST00000954598, ENST00000954599, ENST00000954600

RefSeq mRNA: 1 — MANE Select: NM_005923 NM_005923

CCDS: CCDS5179

Canonical transcript exons

ENST00000359015 — 30 exons

Exon	Start	End
ENSE00000597580	136561533	136561645
ENSE00000764388	136558800	136558876
ENSE00000764408	136562503	136562615
ENSE00000764410	136567631	136567874
ENSE00000764414	136592173	136592341
ENSE00000764416	136601802	136601979
ENSE00000764417	136605209	136605366
ENSE00000764418	136611282	136611387
ENSE00000764419	136613120	136613256
ENSE00000764421	136622848	136622981
ENSE00000764425	136656307	136656460
ENSE00000764426	136659219	136659378
ENSE00000764427	136669283	136669395
ENSE00000764428	136694140	136694310
ENSE00000764429	136695951	136696057
ENSE00000764430	136697219	136697387
ENSE00000764432	136720450	136720589
ENSE00000798893	136592437	136592614
ENSE00000798894	136698489	136698682
ENSE00001013007	136705110	136705133
ENSE00001169933	136791710	136792477
ENSE00001365318	136601022	136601042
ENSE00001511507	136580301	136580406
ENSE00001838560	136557046	136557818
ENSE00003487215	136650984	136651091
ENSE00003568765	136642520	136642569
ENSE00003613222	136614159	136614286
ENSE00003630818	136639543	136639638
ENSE00003672122	136637325	136637406
ENSE00003680119	136583555	136583740

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.7201 / max 416.4947, expressed in 1484 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75798	5.1749	1041
75802	3.0750	1144
75799	2.2143	683
75800	0.1764	67
75801	0.0795	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.71	gold quality
decidua	UBERON:0002450	97.27	gold quality
pancreatic ductal cell	CL:0002079	97.14	gold quality
adrenal cortex	UBERON:0001235	96.96	gold quality
right adrenal gland	UBERON:0001233	96.90	gold quality
left adrenal gland	UBERON:0001234	96.90	gold quality
left adrenal gland cortex	UBERON:0035825	96.84	gold quality
right adrenal gland cortex	UBERON:0035827	96.84	gold quality
adrenal gland	UBERON:0002369	96.42	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.29	silver quality
esophagus squamous epithelium	UBERON:0006920	96.17	gold quality
parietal pleura	UBERON:0002400	96.15	gold quality
visceral pleura	UBERON:0002401	95.77	gold quality
middle temporal gyrus	UBERON:0002771	95.68	gold quality
tibia	UBERON:0000979	95.60	gold quality
amniotic fluid	UBERON:0000173	95.59	gold quality
pleura	UBERON:0000977	95.59	gold quality
choroid plexus epithelium	UBERON:0003911	95.56	gold quality
cervix squamous epithelium	UBERON:0006922	95.47	silver quality
palpebral conjunctiva	UBERON:0001812	94.59	gold quality
adrenal tissue	UBERON:0018303	94.48	gold quality
epithelial cell of pancreas	CL:0000083	94.22	gold quality
squamous epithelium	UBERON:0006914	94.21	gold quality
lateral globus pallidus	UBERON:0002476	94.14	gold quality
left ovary	UBERON:0002119	94.13	gold quality
germinal epithelium of ovary	UBERON:0001304	93.98	gold quality
inferior olivary complex	UBERON:0002127	93.78	silver quality
gingival epithelium	UBERON:0001949	93.51	gold quality
epithelium of esophagus	UBERON:0001976	93.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	11.77
E-MTAB-6678	yes	8.33
E-ANND-3	yes	6.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, IRF6, NKX3-1, RB1, SP1, TP53

miRNA regulators (miRDB)

110 targeting MAP3K5, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
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

Literature-anchored findings (GeneRIF, showing 40)

• Ask1 has a caspase-independent killing function independent of kinase activity and activable by interaction with Daxx. Induced after translocation of Daxx from the nucleus to the cytoplasm, which occurs following activation of the death receptor Fas. (PMID:11493600)
• role in activating the JNK and p38 MAP kinase cascades in response to environmental stresses such as reactive oxygen species (PMID:12189133)
• ASK1 binds to PKR and is involved in apoptosis signalling pathways (PMID:12473108)
• Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH(2)-terminal kinase. (PMID:12482984)
• Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis through this enzyme. (PMID:12556535)
• ASK1 is one of the factors involved in the caspase-independent pathway of LTbetaR-induced cell death. (PMID:12566458)
• These data suggest that AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of inhibitor 14-3-3 from ASK1, a novel mechanism by which TNF-alpha activates ASK1. (PMID:12813029)
• glucose deprivation activates the ASK1-SEK1-JNK1-HIPK1 pathway, relocalizing Daxx from the nucleus to the cytoplasm, where Daxx binds to ASK1, and subsequently leads to ASK1 oligomerization (PMID:12968034)
• results suggest that nitric oxide mediates the interferon-gamma-induced inhibition of apoptosis signal regulating kinase 1(ASK1) in L929 cells through a thiolredox mechanism (PMID:14668338)
• ASK1 is regulated by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation (PMID:14688258)
• apoptosis signal-regulating kinase 1 binds directly to retinoblastoma protein and has roles in apoptotic signaling and cell cycle (PMID:15210709)
• ASK1 signaling is activated by PP5, which is regulated by mTOR (PMID:15218033)
• apoptosis signal-regulating kinase 1 is activated by S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system (PMID:15246877)
• AIP1 is a novel transducer in TNF-induced TRAF2-dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling (PMID:15310755)
• PP5 plays an important role in the survival of cells in a low oxygen environment by suppressing a hypoxia-induced ASK-1/MKK4/JNK signaling cascade that promotes an apoptotic response (PMID:15328343)
• Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis. (PMID:15670787)
• TNFalpha-induced desumoylation and cytoplasmic translocation of HIPK1 are critical in TNFalpha-induced ASK1-JNK/p38 activation (PMID:15701637)
• PKD is a critical mediator in H2O2- but not TNF-induced ASK1-JNK signaling (PMID:15755722)
• Hsp90-Akt forms a complex with ASK1 and protect vascular endothelium from stress-induced apoptosis. (PMID:15782121)
• ASK1 kinase is a central player upstream of p38 MAPK activation when secreted Helicobacter pylori antigen HP0175 effects induction of apopotosis in human gastric epithelial cell line AGS. (PMID:15843568)
• ASK1-p38 cascade regulates the innate immunity of the skin by forming an immune barrier consisting of hBD, LL37, and TLR2 during epidermal differentiation. (PMID:15864780)
• Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2. (PMID:15925322)
• concomitant induction of E2F1 targets ASK1 and Bim by HDACIs warrants an effective activation of E2F1-dependent apoptosis in response to suberoylanilide hydroxamic acid (PMID:16476732)
• E2 promoter-binding factors regulate the expression of ASK1. overexpression and RNA interference experiments support the requirement of endogenous E2F/DP (E2F dimerization partner) activity for ASK-1 expression. (PMID:16512785)
• This study clearly shows the route from ROS generation by 6-OHDA to initiation of p38/JNK signalling via activation of ASK1 in the studied Parkinson disease model. (PMID:16515547)
• reactive oxygen species generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis. (PMID:16532036)
• Glutathione S-transferase P1-1 attenuate TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) (MAP3K5)autophosphorylation (PMID:16636664)
• TNF-alpha increases mitochondrial ROS and activates ASK1 in human hepaatoma cells and these TNF-alpha-induced phenomena contribute to impaired insulin signaling. (PMID:16644673)
• Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1. (PMID:17210579)
• TNFR2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling (PMID:17220297)
• Current findings for the relationship between pathogenesis and ASK1-MAPK pathways. (PMID:17244475)
• Binding of cyclin-dependent kinase inhibitor 1A to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98 (PMID:17325029)
• ASK1 is activated by arsenic trioxide through reactive oxygen species accumulation and may negatively regulate apoptosis in leukemic cells without activating p38 and JNK (PMID:17331470)
• TNF-induced TRAF2-RIP1-AIP1-ASK1 complex formation and for the activation of ASK1-JNK/p38 apoptotic signaling. (PMID:17389591)
• These results suggest that PP2Cepsilon maintains ASK1 in an inactive state by dephosphorylation in quiescent cells, supporting the possibility that PP2Cepsilon and PP5 play different roles in H2O2-induced regulation of ASK1 activity. (PMID:17456047)
• Gemin5 functions as a scaffold protein for the ASK1-JNK1 signaling module and thereby potentiates ASK1-mediated signaling events. (PMID:17541429)
• ghrelin inhibits ASK1-mediated apoptosis and ASK1 activation by a mechanism involving induction of HSP70 (PMID:17543279)
• ASK1 expression levels can be regulated by G alpha13, at least in part via control of ASK1 ubiquitination and degradation (PMID:17595347)
• These results indicate that Ask1 oxidation is required at a step subsequent to activation for signaling downstream of Ask1 after H(2)O(2) treatment. (PMID:17652454)
• discusses the molecular mechanisms by which ASK1 functions in stress and immune responses and discuss the possible involvement of ASK1 in human diseases [review] (PMID:17883330)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k5	ENSDARG00000005416
mus_musculus	Map3k5	ENSMUSG00000071369
rattus_norvegicus	Map3k5	ENSRNOG00000031700
drosophila_melanogaster	Ask1	FBGN0014006
caenorhabditis_elegans		WBGENE00003822

Paralogs (2): MAP3K6 (ENSG00000142733), MAP3K15 (ENSG00000180815)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 5 — Q99683 (reviewed: Q99683)

Alternative names: Apoptosis signal-regulating kinase 1, MAPK/ERK kinase kinase 5

All UniProt accessions (2): A0A8V8TMH5, Q99683

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 signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). 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 MAP2K4/SEK1, 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 JNKs control the transcription factors activator protein-1 (AP-1).

Subunit / interactions. Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN. Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN. Interacts with ERN1 in a TRAF2-dependent manner. Interacts with calcineurin subunit PPP3R1. Interacts with PPM1L. Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5. Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-dependent manner. Interacts with DUSP13A; may positively regulate apoptosis. Interacts with DAXX. Interacts with RC3H2. Interacts with PPIA/CYPA. Interacts with PRMT1; the interaction results in MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation. Interacts with TRAF2; the interaction is inhibited by PRMT1. Interacts with TRIM48. (Microbial infection) Interacts with HIV-1 Nef; this interaction inhibits MAP3K5 signaling.

Subcellular location. Cytoplasm. Endoplasmic reticulum.

Tissue specificity. Abundantly expressed in heart and pancreas.

Post-translational modifications. Phosphorylated at Thr-838 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1. Phosphorylated at Ser-966 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5. Phosphorylation at Ser-966 in response to oxidative stress is negatively regulated by PPIA/CYPA. Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination, leading to proteasomal degradation. Ubiquitinated by RC3H2 in a TRIM48-dependent manner. Methylation at Arg-78 and Arg-80 by PRMT1 promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation. Methylation is blocked by ubiquitination of PRMT1 by TRIM48.

Activity regulation. Activated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C-terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase. Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-838 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1. Phosphorylation of Ser-966 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site. SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Once activated targeted for proteasomal degradation by RC3H2-mediated ubiquitination.

Induction. By TNF. Inhibited by HIV-1 Nef.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q99683-1	1	yes
Q99683-2	2

RefSeq proteins (1): NP_005914* (*=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

Enzyme classification (BRENDA):

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

Substrate kinetics (BRENDA)

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

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

Catalyzed reactions (Rhea), 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 (94 total): helix 31, strand 20, modified residue 11, mutagenesis site 8, turn 7, sequence variant 5, region of interest 3, binding site 2, compositionally biased region 2, chain 1, domain 1, splice variant 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
6E2N	X-RAY DIFFRACTION	2.1
5ULM	X-RAY DIFFRACTION	2.1
4BF2	X-RAY DIFFRACTION	2.11
7MU6	X-RAY DIFFRACTION	2.17
6E2M	X-RAY DIFFRACTION	2.25
6VRE	X-RAY DIFFRACTION	2.29
7MU7	X-RAY DIFFRACTION	2.3
2CLQ	X-RAY DIFFRACTION	2.3
4BHN	X-RAY DIFFRACTION	2.3
4BIE	X-RAY DIFFRACTION	2.36
6EJL	X-RAY DIFFRACTION	2.38
6E2O	X-RAY DIFFRACTION	2.39
3VW6	X-RAY DIFFRACTION	2.4
4BIB	X-RAY DIFFRACTION	2.43
5UOX	X-RAY DIFFRACTION	2.5
5V24	X-RAY DIFFRACTION	2.5
6OYW	X-RAY DIFFRACTION	2.6
4BIC	X-RAY DIFFRACTION	2.62
5VIL	X-RAY DIFFRACTION	2.64
6XIH	X-RAY DIFFRACTION	2.65
5UOR	X-RAY DIFFRACTION	2.75
4BID	X-RAY DIFFRACTION	2.8
6OYT	X-RAY DIFFRACTION	2.82
5VIO	X-RAY DIFFRACTION	2.84
5UP3	X-RAY DIFFRACTION	2.95
5V19	X-RAY DIFFRACTION	3.1
8QGY	ELECTRON MICROSCOPY	3.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99683-F1	73.87	0.30

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): 803 (proton acceptor)

Ligand- & substrate-binding residues (2): 709; 686–694

Post-translational modifications (11): 78, 80, 83, 718, 813, 838, 842, 958, 966, 1029, 1033

Mutagenesis-validated functional residues (8):

Position	Phenotype
32	no effect on methylation by prmt1.
78	reduced methylation by prmt1. abolishes methylation by prmt1 and prmt1-mediated inhibition of mapk35 activation; when as
80	reduced methylation by prmt1. abolishes methylation by prmt1 and prmt1-mediated inhibition of mapk35 activation; when as
709	loss of kinase activity. inhibits activation of jnk and apoptosis mediated by tnfrsf6 and daxx. does not affect interact
709	loss of kinase activity. abolishes daxx-mediated apoptosis. loss of rc3h2-mediated ubiquitination.
838	does not affect interaction with trim48.
966	enhanced induction of apoptosis, increased kinase activity, and loss of ywhag binding.
1033	enhanced induction of apoptosis and increased kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 410 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, LU_IL4_SIGNALING, TGCACTT_MIR519C_MIR519B_MIR519A, KEGG_MAPK_SIGNALING_PATHWAY, GCANCTGNY_MYOD_Q6, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, AREB6_01, RIZKI_TUMOR_INVASIVENESS_3D_DN, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN

GO Biological Process (31): MAPK cascade (GO:0000165), response to ischemia (GO:0002931), JNK cascade (GO:0007254), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), cellular response to amino acid starvation (GO:0034198), response to endoplasmic reticulum stress (GO:0034976), neuron intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0036480), p38MAPK cascade (GO:0038066), positive regulation of apoptotic process (GO:0043065), innate immune response (GO:0045087), positive regulation of myoblast differentiation (GO:0045663), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of JNK cascade (GO:0046330), neuron apoptotic process (GO:0051402), stress-activated MAPK cascade (GO:0051403), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), cellular response to hydrogen peroxide (GO:0070301), cellular response to tumor necrosis factor (GO:0071356), endothelial cell apoptotic process (GO:0072577), cellular senescence (GO:0090398), apoptotic signaling pathway (GO:0097190), programmed necrotic cell death (GO:0097300), positive regulation of p38MAPK cascade (GO:1900745), cellular response to reactive nitrogen species (GO:1902170), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), immune system process (GO:0002376), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), regulation of programmed cell death (GO:0043067), positive regulation of MAPK cascade (GO:0043410)

GO Molecular Function (17): magnesium ion binding (GO:0000287), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), JUN kinase kinase kinase activity (GO:0004706), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), external side of plasma membrane (GO:0009897), protein-containing complex (GO:0032991), protein kinase complex (GO:1902911), IRE1-TRAF2-ASK1 complex (GO:1990604), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular Senescence	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	4
apoptotic process	3
intrinsic apoptotic signaling pathway	2
protein kinase activity	2
protein binding	2
cellular anatomical structure	2
cytoplasm	2
intracellular signaling cassette	1
response to stress	1
cardiac muscle cell apoptotic process	1
positive regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
cellular response to starvation	1
response to amino acid starvation	1
cellular response to stress	1
intrinsic apoptotic signaling pathway in response to oxidative stress	1
neuron apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
immune response	1
defense response to symbiont	1
myoblast differentiation	1
positive regulation of cell differentiation	1
regulation of myoblast differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
stress-activated protein kinase signaling cascade	1
response to endoplasmic reticulum stress	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1
metal ion binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1

Protein interactions and networks

STRING

2292 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K5	TXN	P10599	997
MAP3K5	TRAF2	Q12933	994
MAP3K5	DAXX	Q9UER7	993
MAP3K5	ERN1	O75460	988
MAP3K5	ARRB2	P32121	969
MAP3K5	TXN2	Q99757	961
MAP3K5	MAP2K4	P45985	938
MAP3K5	PRDX1	P35703	890
MAP3K5	RB1CC1	Q8TDY2	879
MAP3K5	JUN	P05412	858
MAP3K5	PARK7	Q99497	847
MAP3K5	TXNIP	Q9H3M7	840
MAP3K5	TRAF6	Q9Y4K3	806
MAP3K5	DAB2IP	Q5VWQ8	804
MAP3K5	AKT1	P31749	804

IntAct

189 interactions, top by confidence:

A	B	Type	Score
DAXX	MAP3K5	psi-mi:“MI:0915”(physical association)	0.810
DAXX	MAP3K5	psi-mi:“MI:0403”(colocalization)	0.810
DAXX	MAP3K5	psi-mi:“MI:2364”(proximity)	0.810
MAP3K5	MAP3K5	psi-mi:“MI:0407”(direct interaction)	0.780
MAP3K5	MAP3K5	psi-mi:“MI:0915”(physical association)	0.780
YWHAZ	MAP3K5	psi-mi:“MI:0915”(physical association)	0.780
YWHAZ	MAP3K5	psi-mi:“MI:0914”(association)	0.780
MAP3K5	MAP2K3	psi-mi:“MI:0915”(physical association)	0.760
MAP2K3	MAP3K5	psi-mi:“MI:0915”(physical association)	0.760
MAP3K5	MAP2K3	psi-mi:“MI:0914”(association)	0.760
MAP3K5	YWHAH	psi-mi:“MI:0915”(physical association)	0.740
MAP3K5	YWHAH	psi-mi:“MI:0914”(association)	0.740
YWHAG	MAP3K5	psi-mi:“MI:0914”(association)	0.730
MAP3K5	YWHAB	psi-mi:“MI:0915”(physical association)	0.720
MAP3K5	YWHAB	psi-mi:“MI:0914”(association)	0.720
MAP3K5	TRAF2	psi-mi:“MI:0915”(physical association)	0.700
MAP3K5	TRAF2	psi-mi:“MI:0407”(direct interaction)	0.700
TRAF2	MAP3K5	psi-mi:“MI:0915”(physical association)	0.700
MAP3K5	TXN	psi-mi:“MI:0915”(physical association)	0.680

BioGRID (354): TXN2 (Affinity Capture-Western), TXN2 (Co-fractionation), TXN (Affinity Capture-Western), TXN (Affinity Capture-Western), MAP3K5 (Affinity Capture-Western), ATAD3A (Affinity Capture-MS), NACC1 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), MAP3K5 (Affinity Capture-Western), MAP3K5 (Affinity Capture-Western), SIAH1 (Reconstituted Complex), SIAH1 (Biochemical Activity), MAP3K5 (Affinity Capture-MS), MAP3K5 (Affinity Capture-Western)

ESM2 similar proteins: A0A1P8AWH8, A2Y8B9, F1QR43, F4JG10, F4JVN6, F4KFT7, O18756, O22975, O23617, O80574, O80596, O80738, O94923, Q06402, Q0VC13, Q0WUI9, Q10MJ1, Q1PET6, Q3U1V6, Q43093, Q43847, Q5IH13, Q5IH14, Q5MAU8, Q5VS72, Q6DHV7, Q6YXW6, Q6ZHE5, Q80SY6, Q8L7N4, Q8LB01, Q8VYP9, Q8VZF3, Q8W4K1, Q8W519, Q94AH8, Q94AS5, Q94E75, Q96DG6, Q99683

Diamond homologs: A0A078CGE6, A0A194W8T8, A2AQW0, A2QHV0, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A7A1P0, A8XJW8, A9RVK2, A9SY39, B0XXN8, B5VNQ3, E9Q3S4, F4HRJ4, G4N7X0, G4NDR3, O08648, O14047, O14299, O22040, O22042, O35099, O54748, O61122, O74304, O81472, O95382, P23561, P25390, P28829, P41892, P53349, P53599, Q01389, Q03497

SIGNOR signaling

60 interactions.

A	Effect	B	Mechanism
AKT2	“down-regulates activity”	MAP3K5	phosphorylation
AKT	“down-regulates activity”	MAP3K5	phosphorylation
RAF1	down-regulates	MAP3K5	binding
FAS	up-regulates	MAP3K5	binding
MAP3K5	“up-regulates quantity by stabilization”	DAXX	phosphorylation
PPP5C	“down-regulates activity”	MAP3K5	dephosphorylation
MAP3K5	up-regulates	MAP2K7	phosphorylation
SLK	up-regulates	MAP3K5	phosphorylation
MAPK1	up-regulates	MAP3K5
MAP3K5	up-regulates	CDKN1A	phosphorylation
PPM1L	down-regulates	MAP3K5	dephosphorylation
MAP3K5	“up-regulates activity”	MAP3K5	phosphorylation
MAP3K5	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K5	up-regulates	ZNF622	phosphorylation
JAK2	down-regulates	MAP3K5	phosphorylation
PTPN11	up-regulates	MAP3K5	dephosphorylation
PIM1	down-regulates	MAP3K5	phosphorylation
MAP3K5	up-regulates	DAXX	phosphorylation
ROS	up-regulates	MAP3K5
AKT1	“down-regulates activity”	MAP3K5	phosphorylation
DAB2IP	“up-regulates activity”	MAP3K5	binding
PP2Ca_R1A_Bd	“up-regulates activity”	MAP3K5	dephosphorylation
PIM	down-regulates	MAP3K5	phosphorylation
MAP3K6	“up-regulates activity”	MAP3K5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
Activation of BAD and translocation to mitochondria	9	91.4×	5e-14
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	9	80.6×	1e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	62.7×	6e-10
Activation of BH3-only proteins	9	59.6×	2e-12
FOXO-mediated transcription	9	40.3×	7e-11
Intrinsic Pathway for Apoptosis	9	35.1×	3e-10
RHO GTPases activate PKNs	7	29.6×	1e-07
Attenuation phase	5	27.2×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	5	35.9×	9e-05
cellular response to vascular endothelial growth factor stimulus	5	32.3×	1e-04
response to heat	6	29.1×	3e-05
protein targeting	5	21.1×	5e-04
cellular response to heat	5	19.8×	7e-04
ERK1 and ERK2 cascade	5	18.3×	9e-04
regulation of protein localization	5	11.8×	5e-03
positive regulation of cell growth	5	10.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	6
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

5494 predictions. Top by Δscore:

Variant	Effect	Δscore
6:136558877:C:CC	acceptor_gain	1.0000
6:136561531:AC:A	donor_gain	1.0000
6:136561532:CC:C	donor_gain	1.0000
6:136561532:CCCGG:C	donor_gain	1.0000
6:136561642:ATTT:A	acceptor_gain	1.0000
6:136561642:ATTTC:A	acceptor_loss	1.0000
6:136561643:TTT:T	acceptor_gain	1.0000
6:136561644:TT:T	acceptor_gain	1.0000
6:136561645:TCT:T	acceptor_loss	1.0000
6:136561646:C:CC	acceptor_gain	1.0000
6:136561646:C:T	acceptor_loss	1.0000
6:136561647:T:A	acceptor_loss	1.0000
6:136562431:T:TA	donor_gain	1.0000
6:136562519:A:AC	donor_gain	1.0000
6:136562519:AAG:A	donor_gain	1.0000
6:136562520:A:C	donor_gain	1.0000
6:136562614:AT:A	acceptor_gain	1.0000
6:136562616:C:CC	acceptor_gain	1.0000
6:136580295:TCTGA:T	donor_loss	1.0000
6:136580296:CTGA:C	donor_loss	1.0000
6:136580297:TGA:T	donor_loss	1.0000
6:136580298:GACCT:G	donor_loss	1.0000
6:136580299:ACCT:A	donor_loss	1.0000
6:136580300:CCTGG:C	donor_loss	1.0000
6:136580302:TGGA:T	donor_gain	1.0000
6:136580405:ACCT:A	acceptor_loss	1.0000
6:136580408:T:G	acceptor_loss	1.0000
6:136583549:A:AC	donor_gain	1.0000
6:136583549:ACTT:A	donor_loss	1.0000
6:136583550:C:CC	donor_gain	1.0000

AlphaMissense

9095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:136580359:A:C	F1153L	1.000
6:136580359:A:T	F1153L	1.000
6:136580360:A:C	F1153C	1.000
6:136580360:A:G	F1153S	1.000
6:136580361:A:G	F1153L	1.000
6:136580370:G:C	H1150D	1.000
6:136601881:T:A	R926S	1.000
6:136601881:T:G	R926S	1.000
6:136601882:C:G	R926T	1.000
6:136601957:G:T	P901H	1.000
6:136601975:C:T	G895E	1.000
6:136601976:C:G	G895R	1.000
6:136601976:C:T	G895R	1.000
6:136605212:G:C	F892L	1.000
6:136605212:G:T	F892L	1.000
6:136605213:A:C	F892C	1.000
6:136605213:A:G	F892S	1.000
6:136605214:A:G	F892L	1.000
6:136605219:G:T	A890D	1.000
6:136605245:A:C	F881L	1.000
6:136605245:A:T	F881L	1.000
6:136605247:A:G	F881L	1.000
6:136605247:A:T	F881I	1.000
6:136605249:G:T	P880Q	1.000
6:136605265:C:G	A875P	1.000
6:136605267:A:C	M874R	1.000
6:136605267:A:T	M874K	1.000
6:136605269:T:A	E873D	1.000
6:136605269:T:G	E873D	1.000
6:136605281:A:C	C869W	1.000

dbSNP variants (sampled 300 via entrez): RS1000020329 (6:136578430 A>G), RS1000021841 (6:136645088 C>G), RS1000031322 (6:136623824 C>T), RS1000057609 (6:136595262 C>T), RS1000070415 (6:136688770 A>G), RS1000078169 (6:136599933 G>T), RS1000102221 (6:136772982 A>C,G,T), RS1000115453 (6:136757664 T>C), RS1000129068 (6:136782961 G>A,T), RS1000166546 (6:136771624 T>A,G), RS1000173498 (6:136764361 T>C), RS1000193220 (6:136683055 A>G), RS1000193416 (6:136629366 A>G), RS1000227970 (6:136766945 T>C), RS1000233116 (6:136725363 C>T)

Disease associations

OMIM: gene MIM:602448 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006611_75	HDL cholesterol	4.000000e-10
GCST010242_137	HDL cholesterol levels	2.000000e-12
GCST90002381_163	Eosinophil count	1.000000e-13
GCST90002387_293	Immature fraction of reticulocytes	2.000000e-09
GCST90002393_98	Monocyte count	3.000000e-13
GCST90002398_410	Neutrophil count	7.000000e-14
GCST90002407_528	White blood cell count	2.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004842	eosinophil count
EFO:0005091	monocyte count
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5285 (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: 4,715 (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
CHEMBL3916717	SELONSERTIB	3	1,422
CHEMBL603469	LESTAURTINIB	3
CHEMBL495727	AT-9283	2	1,376
CHEMBL2140408	AMG-900	1	675
CHEMBL4289017	PF-03814735	1	537
CHEMBL571948	Y-39983	1	705

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs9376230	Efficacy	3	hydroxyurea	Beta-thalassemia and related diseases
rs9483947	Efficacy	3	hydroxyurea	Beta-thalassemia and related diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9376230	MAP3K5	3	2.00	1	hydroxyurea
rs9483947	MAP3K5	3	1.50	1	hydroxyurea

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE11 family

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

Ligand	Action	Affinity	Parameter
GS-444217	Inhibition	8.54	pIC50
selonsertib	Inhibition	8.49	pIC50
compound 10 [PMID: 23147077]	Inhibition	8.0	pIC50
MSC2032964A	Inhibition	7.03	pIC50
compound 26 [PMID: 31710475]	Inhibition	6.83	pIC50

Binding affinities (BindingDB)

140 measured of 233 human assays (233 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-[4-(methylcarbamoyl)piperidin-1-yl]pyridine-2-carboxamide	IC50	0.4 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-piperidin-1-yl-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	0.7 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
5-(3-cyanoazetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	0.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.1 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(3-cyano-3-methylazetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.4 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
1-[3-(4-Cyclopropylimidazol-1-yl)cyclobutyl]-3-[6-(4-isopropyl-1,2,4-triazol-3-yl)-2-pyridyl]imidazolidin-2-one, isomer 2	IC50	1.47 nM	US-10370352: Cyclobutyl-imidazolidinone compounds
4-(4-cyclopropylimidazol-1-yl)-5-[4-(trifluoromethyl)piperidin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.5 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-hydroxy-3-methylazetidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.69 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
5-(azetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.7 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-[3-(difluoromethyl)azetidin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.7 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(4-cyanopiperidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.7 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-fluoropiperidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.7 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
Staurosporine	KD	1.7 nM
5-(azetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-[4-(1,1,1-trifluoropropan-2-yl)-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.7 nM	US-10307427: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.8 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-(3-methoxy-3-methylazetidin-1-yl)pyridine-2-carboxamide	IC50	1.8 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-cyclopropylpiperazin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.8 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-[4-(cyclopropylmethyl)piperazin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.8 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
N-[4-(4-cyclopropylimidazol-1-yl)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.8 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
1-(3-(4-(tert-Butyl)-1H-imidazol-1-yl)cyclobutyl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)imidazolidin-2-one	IC50	1.84 nM	US-10370352: Cyclobutyl-imidazolidinone compounds
4-(4-cyclopropylimidazol-1-yl)-5-(dimethylamino)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.88 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-pyrrolidin-1-ylpyridine-2-carboxamide	IC50	1.9 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
5-(3-cyano-3-methylazetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridine-2-carboxamide	IC50	1.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-methoxypyrrolidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(1,4-oxazepan-4-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-morpholin-4-ylazetidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
N-(3-bromo-1-cyclopropylpyrrolo[3,2-c]pyridin-6-yl)-4-[(2R)-1,2-dihydroxypropan-2-yl]benzamide	IC50	2 nM	US-8802695: Apoptosis signal-regulating kinase 1 inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-piperidin-1-ylpyridine-2-carboxamide	IC50	2 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-[3-(methoxymethyl)azetidin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-methoxy-3-methylazetidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-methylpiperazin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.1 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3,3-difluoropyrrolidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.1 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.1 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
1-[3-(1-Isopropylpyrazol-4-yl)cyclobutyl]-3-[6-(4-isopropyl-1,2,4-triazol-3-yl)-2-pyridyl]imidazolidin-2-one	IC50	2.17 nM	US-10370352: Cyclobutyl-imidazolidinone compounds
4-(4-cyclopropylimidazol-1-yl)-5-pyrrolidin-1-yl-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-hydroxypyrrolidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-[3-(difluoromethyl)azetidin-1-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(4-cyanopiperidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-methoxy-4-methylpiperidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-pyrrolidin-1-yl-N-[2-[4-(1,1,1-trifluoropropan-2-yl)-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.2 nM	US-10307427: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-(3-morpholin-4-ylazetidin-1-yl)pyridine-2-carboxamide	IC50	2.3 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(4-methoxypiperidin-1-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.3 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-[4-(methylcarbamoyl)piperidin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.3 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(3-oxo-5,6,8,8a-tetrahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-7-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.3 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-(azetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.4 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-5-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	2.4 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-(4-hydroxy-4-methylpiperidin-1-yl)pyridine-2-carboxamide	IC50	2.5 nM	US-9051313: Apoptosis signal-regulating kinase inhibitors

ChEMBL bioactivities

1869 potent at pChembl≥5 of 1898 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4283739
9.52	IC50	0.3	nM	CHEMBL5787727
9.49	IC50	0.32	nM	CHEMBL4290518
9.40	IC50	0.4	nM	CHEMBL3969572
9.40	IC50	0.398	nM	CHEMBL5746514
9.38	IC50	0.42	nM	CHEMBL4294318
9.30	IC50	0.5	nM	CHEMBL5559492
9.30	IC50	0.5	nM	CHEMBL5559703
9.30	IC50	0.5	nM	CHEMBL6039009
9.22	IC50	0.6	nM	CHEMBL5895109
9.22	IC50	0.6	nM	CHEMBL5760486
9.16	IC50	0.69	nM	STAUROSPORINE
9.15	IC50	0.7	nM	CHEMBL3683270
9.15	IC50	0.7	nM	CHEMBL4083562
9.15	IC50	0.7	nM	CHEMBL5561248
9.15	IC50	0.7	nM	CHEMBL5946199
9.12	Kd	0.75	nM	CHEMBL5780163
9.07	Kd	0.86	nM	CHEMBL5862012
9.05	IC50	0.9	nM	CHEMBL5563790
9.05	IC50	0.9	nM	CHEMBL3975211
9.05	IC50	0.9	nM	CHEMBL5802582
9.05	IC50	0.9	nM	CHEMBL5803572
9.03	IC50	0.93	nM	CHEMBL5562668
9.00	IC50	1	nM	CHEMBL4282644
9.00	IC50	1	nM	CHEMBL4868362
9.00	IC50	1	nM	CHEMBL5559907
9.00	IC50	1	nM	CHEMBL5565908
9.00	IC50	1	nM	CHEMBL5557520
8.98	IC50	1.05	nM	CHEMBL5843273
8.96	IC50	1.1	nM	CHEMBL5559017
8.96	IC50	1.1	nM	CHEMBL5562336
8.96	IC50	1.1	nM	CHEMBL3922577
8.94	IC50	1.14	nM	CHEMBL5567699
8.92	IC50	1.2	nM	CHEMBL3902880
8.90	IC50	1.26	nM	CHEMBL5937217
8.86	IC50	1.37	nM	CHEMBL5532500
8.85	IC50	1.4	nM	CHEMBL3893968
8.85	IC50	1.4	nM	CHEMBL5958731
8.84	IC50	1.44	nM	CHEMBL3683259
8.82	IC50	1.5	nM	CHEMBL4278211
8.82	IC50	1.5	nM	CHEMBL3976987
8.80	IC50	1.58	nM	CHEMBL3683260
8.80	IC50	1.6	nM	CHEMBL5795972
8.80	IC50	1.6	nM	CHEMBL5967167
8.80	IC50	1.58	nM	CHEMBL5770629
8.78	IC50	1.65	nM	CHEMBL5559945
8.77	IC50	1.69	nM	CHEMBL3683262
8.77	IC50	1.7	nM	CHEMBL3683265
8.77	IC50	1.7	nM	CHEMBL3930015
8.77	IC50	1.7	nM	CHEMBL3917308

PubChem BioAssay actives

568 with measured affinity, of 1970 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
2-methoxy-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-5-sulfamoylbenzamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0001	uM
5-(ethylsulfonylamino)-2-methoxy-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0003	uM
4-methoxy-6-methyl-3-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzene-1,3-dicarboxamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0004	uM
5-(4-cyclopropylimidazol-1-yl)-N-(5,6-dihydrotriazolo[1,5-d][1,4]benzoxazepin-8-yl)-2-fluoro-4-methylbenzamide	2073532: Inhibition of ASK1 (unknown origin) incubated for 120 mins	ic50	0.0005	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-spiro[6H-[1,2,4]triazolo[4,3-d][1,4]benzoxazepine-5,1’-cyclopropane]-8-ylbenzamide	2073532: Inhibition of ASK1 (unknown origin) incubated for 120 mins	ic50	0.0005	uM
N-[4-(4-cyclopropylimidazol-1-yl)-2-pyridinyl]-6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridine-2-carboxamide	2073538: Inhibition of human recombinant ASK1 by HTRF assay	ic50	0.0007	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1410111: Inhibition of ASK1 (unknown origin) by HTRF assay	ic50	0.0007	uM
4-(4-cyclopropylimidazol-1-yl)-5-piperidin-1-yl-N-[2-[4-(1,1,1-trifluoropropan-2-yl)-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	1469855: Inhibition of recombinant human ASK1 using STK3 peptide as substrate incubated for 30 mins followed by ATP addition measured for 3 hrs by TR-FRET assay	ic50	0.0007	uM
6-(4-cyclopropylimidazol-1-yl)-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3H-isoindol-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0009	uM
7-(4-cyclopropylimidazol-1-yl)-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]phthalazin-1-one	2073531: Inhibition of ASK1 (unknown origin) preincubated with compound for 30 mins followed by ATP addition and measured after 120 mins by HTRF analysis	ic50	0.0009	uM
5-(4-cyclopropylimidazol-1-yl)-N-[6-(5,5-dimethyl-6,7-dihydropyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-pyridinyl]-2-fluoro-4-methylbenzamide	2073530: Inhibition of ASK1 (unknown origin) incubated for 0.5 to 5 hrs by TR-FRET assay	ic50	0.0010	uM
4-methoxy-3-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzene-1,3-dicarboxamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0010	uM
3-methoxy-1-methyl-N-[6-[4-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0010	uM
(2R)-4-(6-cyclopropyl-3-pyridinyl)-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]morpholine-2-carboxamide	1721900: Binding affinity to ASK1 (unknown origin)	kd	0.0010	uM
5-(4-cyclopropylimidazol-1-yl)-N-[3,4-dideuterio-6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-2-fluoro-4-methylbenzamide	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0010	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[4-(1,1,1,2,3,3,3-heptadeuteriopropan-2-yl)-1,2,4-triazol-3-yl]-2-pyridinyl]-4-methylbenzamide	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0010	uM
6-(4-cyclopropylimidazol-1-yl)-3-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]chromen-4-one	2073531: Inhibition of ASK1 (unknown origin) preincubated with compound for 30 mins followed by ATP addition and measured after 120 mins by HTRF analysis	ic50	0.0011	uM
3-(4-cyclopropylimidazol-1-yl)-2-deuterio-6-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzamide	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0011	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[4-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)-1,2,4-triazol-3-yl]-2-pyridinyl]-4-methylbenzamide	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0011	uM
6-(4-cyclopropylimidazol-1-yl)-1-methyl-3-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]quinolin-4-one	2073531: Inhibition of ASK1 (unknown origin) preincubated with compound for 30 mins followed by ATP addition and measured after 120 mins by HTRF analysis	ic50	0.0014	uM
2-methoxy-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-5-sulfamoylbenzamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0015	uM
7-(4-cyclopropylimidazol-1-yl)-6-methoxy-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]isoquinolin-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0016	uM
5-(1-cyclopropylpyrazol-4-yl)-N-[6-(4-cyclopropyl-1,2,4-triazol-3-yl)-2-pyridinyl]-1-[(2-fluorophenyl)methyl]-2-oxopyridine-3-carboxamide	2003067: Inhibition of human recombinant ASK1 using MBP as substrate preincubated for 1 hr followed by reagent addition incubated for 40 mins by ATP-Glo kinase assay	ic50	0.0017	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-2-pyridinyl]benzamide	2073530: Inhibition of ASK1 (unknown origin) incubated for 0.5 to 5 hrs by TR-FRET assay	ic50	0.0018	uM
7-(4-cyclopropylimidazol-1-yl)-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3,4-dihydroisoquinolin-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0018	uM
5-(4-cyclopropylimidazol-1-yl)-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3H-isoindol-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0018	uM
5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5R)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-2-pyridinyl]-2-fluoro-4-methylbenzamide	2073530: Inhibition of ASK1 (unknown origin) incubated for 0.5 to 5 hrs by TR-FRET assay	ic50	0.0019	uM
1-[5-(dimethylamino)-3-pyridinyl]-3-methoxy-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]pyrazole-4-carboxamide	1648778: Inhibition of human ASK1 using myelin basic protein substrate preincubated for 20 mins before [33P]-ATP addition and measured after 2 hrs by filter-binding method	ic50	0.0019	uM
1-ethyl-3-methoxy-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0020	uM
3-methoxy-1-(2-methoxyethyl)-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0020	uM
1-(cyclopropylmethyl)-3-methoxy-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0020	uM
4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]morpholine-2-carboxamide	1721872: Inhibition of ASK1 (unknown origin)	ic50	0.0020	uM
N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]quinoline-8-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0020	uM
tert-butyl N-[2-[2-(benzotriazol-1-yloxy)ethoxy]ethyl]-N-[(1R,2R,5S,8R,9R,10R,12R,16R,17S,18S,21S)-16-hydroxy-1,2,17-trimethyl-14-oxo-8,18-bis(prop-1-en-2-yl)-13-oxapentacyclo[10.8.1.02,10.05,9.017,21]henicosane-5-carbonyl]carbamate	2073544: Inhibition of N-terminal his-tagged human ASK1 (649 to 946 residues) expressed in Escherichia coli using [gamma-32p]ATP as substrate by liquid scintillation counting analysis	ic50	0.0020	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzamide	1721899: Inhibition of ASK1 (unknown origin) by cell based assay	ec50	0.0020	uM
7-(4-cyclopropylimidazol-1-yl)-6-methyl-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3,4-dihydroisoquinolin-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0022	uM
4-methoxy-1-N-methyl-3-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzene-1,3-dicarboxamide	1404085: Inhibition of recombinant full length human GST-tagged ASK1 expressed in baculovirus expression system using STK3 peptide substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of 1 mM ATP by HTRF assay	ic50	0.0024	uM
3-methoxy-1-methyl-N-[6-(3-propan-2-ylimidazol-4-yl)-2-pyridinyl]pyrazole-4-carboxamide	1648778: Inhibition of human ASK1 using myelin basic protein substrate preincubated for 20 mins before [33P]-ATP addition and measured after 2 hrs by filter-binding method	ic50	0.0024	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[(6S)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-d][1,4]benzoxazepin-8-yl]benzamide	2073532: Inhibition of ASK1 (unknown origin) incubated for 120 mins	ic50	0.0025	uM
7-(4-cyclopropylimidazol-1-yl)-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]isoquinolin-1-one	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0027	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-2-pyridinyl]benzamide	2073530: Inhibition of ASK1 (unknown origin) incubated for 0.5 to 5 hrs by TR-FRET assay	ic50	0.0029	uM
4-(4-cyclopropylimidazol-1-yl)-N-[3-(4-cyclopropyl-1,2,4-triazol-3-yl)phenyl]pyridine-2-carboxamide	1691953: Inhibition of ASK1 (unknown origin) by competitive TR-FRET assay	ic50	0.0029	uM
4-(4-cyclopropylimidazol-1-yl)-N-[3-(4-propan-2-yl-1,2,4-triazol-3-yl)phenyl]pyridine-2-carboxamide	2073516: Inhibition of ASK1 (unknown origin)	ic50	0.0029	uM
3-methoxy-1-methyl-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
3-methoxy-1-pyrazin-2-yl-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
3-methoxy-1-(2,2,2-trifluoroethyl)-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
3-methoxy-1-pyridazin-3-yl-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyrazole-4-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
2-methoxy-5-methyl-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]pyridine-3-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
2-methoxy-N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]benzamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM
N-[6-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]quinoxaline-5-carboxamide	1785709: Inhibition of ASK1 (unknown origin) using myelin basic protein as substrate preincubated for 20 mins followed by 33P-ATP addition and measured after 2 hrs	ic50	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Acetylcysteine	decreases reaction, increases phosphorylation, decreases expression, affects phosphorylation, increases activity (+1 more)	5
Cadmium Chloride	decreases reaction, increases expression, increases phosphorylation, decreases expression, increases activity (+1 more)	5
sodium arsenite	increases expression, affects expression, decreases expression, increases activity	4
Acetaminophen	decreases expression, affects cotreatment	3
1-Methyl-4-phenylpyridinium	decreases expression, increases expression, increases phosphorylation, decreases reaction	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
entinostat	increases expression, affects cotreatment	2
salubrinal	affects localization, decreases reaction, increases activity, increases phosphorylation, increases reaction (+4 more)	2
Resveratrol	increases activity, affects cotreatment, increases expression	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression	2
Copper	affects binding, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Glucose	affects binding, increases reaction, increases expression, increases activity, increases phosphorylation	2
Paraquat	affects cotreatment, increases degradation, increases reaction, increases activity, increases expression (+3 more)	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Plant Extracts	decreases reaction, increases phosphorylation, affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, decreases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
moringin	affects cotreatment, increases expression	1
AKT activator SC79	decreases reaction, increases expression	1
4-methylumbelliferone 8-carbaldehyde	decreases reaction, increases phosphorylation	1
KIRA6	decreases reaction, increases phosphorylation	1
geldanamycin	increases expression	1
beta-N-methylamino-L-alanine	increases phosphorylation	1
naringenin	increases expression	1
bisphenol A	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

607 unique, capped per target: 421 binding, 186 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004489	Binding	Binding affinity to human recombinant MAP3K5 expressed in Escherichia coli assessed as thermal shift by differential scanning fluorimetry	Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone. — Bioorg Med Chem
CHEMBL5445297	Functional	Affinity Phenotypic Cellular interaction: (MTT assay (ABCB1-gene-transfected cell line HEK293/pcDNA3.1, Doxorubicin treatment, using 0 uM Selonsertib)) EUB0000695a MAP3K5	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1XH	Abcam A-549 MAP3K5 KO	Cancer cell line	Male
CVCL_D2BR	Abcam HCT 116 MAP3K5 KO	Cancer cell line	Male
CVCL_D8Q3	Ubigene HCT 116 MAP3K5 KO	Cancer cell line	Male
CVCL_E0HA	Ubigene HeLa MAP3K5 KO	Cancer cell line	Female
CVCL_SW71	HAP1 MAP3K5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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