MAPK8

Summary

MAPK8 (mitogen-activated protein kinase 8, HGNC:6881) is a protein-coding gene on chromosome 10q11.22, encoding Mitogen-activated protein kinase 8 (P45983). Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death.

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 5599 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary skin disorder (Moderate, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 34 total
• Druggable target: yes — 50 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001323329

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6881
Approved symbol	MAPK8
Name	mitogen-activated protein kinase 8
Location	10q11.22
Locus type	gene with protein product
Status	Approved
Aliases	JNK, JNK1, SAPK1
Ensembl gene	ENSG00000107643
Ensembl biotype	protein_coding
OMIM	601158
Entrez	5599

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000360332, ENST00000374174, ENST00000374176, ENST00000374179, ENST00000374182, ENST00000374189, ENST00000395611, ENST00000426557, ENST00000429041, ENST00000432379, ENST00000459755, ENST00000469110, ENST00000469879, ENST00000471272, ENST00000476134, ENST00000482840, ENST00000860603

RefSeq mRNA: 17 — MANE Select: NM_001323329 NM_001278547, NM_001278548, NM_001323302, NM_001323320, NM_001323321, NM_001323322, NM_001323323, NM_001323324, NM_001323325, NM_001323326, NM_001323327, NM_001323328, NM_001323329, NM_001323330, NM_001323331, NM_139046, NM_139049

CCDS: CCDS60527, CCDS7223, CCDS7224, CCDS7225, CCDS7226

Canonical transcript exons

ENST00000374189 — 12 exons

Exon	Start	End
ENSE00001462730	48434884	48439360
ENSE00001462753	48306677	48306821
ENSE00002456265	48424088	48424159
ENSE00002457248	48410030	48410168
ENSE00002488171	48420155	48420320
ENSE00003471599	48426380	48426504
ENSE00003534877	48427080	48427143
ENSE00003545352	48425888	48426070
ENSE00003592664	48431193	48431270
ENSE00003638267	48404852	48404981
ENSE00003642339	48409879	48409937
ENSE00003833915	48401612	48401782

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 98.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.3270 / max 459.1372, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104837	30.9007	1821
104838	3.8445	1508
104836	0.5818	339

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.46	gold quality
ganglionic eminence	UBERON:0004023	97.97	gold quality
adrenal tissue	UBERON:0018303	96.12	gold quality
tendon of biceps brachii	UBERON:0008188	94.60	gold quality
calcaneal tendon	UBERON:0003701	94.09	gold quality
tendon	UBERON:0000043	93.92	gold quality
stromal cell of endometrium	CL:0002255	93.77	gold quality
buccal mucosa cell	CL:0002336	93.76	gold quality
ventricular zone	UBERON:0003053	92.46	gold quality
islet of Langerhans	UBERON:0000006	92.33	gold quality
medial globus pallidus	UBERON:0002477	90.90	gold quality
gall bladder	UBERON:0002110	90.85	gold quality
colonic epithelium	UBERON:0000397	90.59	gold quality
pons	UBERON:0000988	90.38	gold quality
left testis	UBERON:0004533	90.38	gold quality
right testis	UBERON:0004534	90.12	gold quality
rectum	UBERON:0001052	90.11	gold quality
testis	UBERON:0000473	89.53	gold quality
prefrontal cortex	UBERON:0000451	89.46	gold quality
left ovary	UBERON:0002119	89.05	gold quality
cerebellar hemisphere	UBERON:0002245	89.05	gold quality
cerebellar cortex	UBERON:0002129	88.98	gold quality
secondary oocyte	CL:0000655	88.87	gold quality
ovary	UBERON:0000992	88.82	gold quality
lower esophagus mucosa	UBERON:0035834	88.73	gold quality
jejunal mucosa	UBERON:0000399	88.62	gold quality
globus pallidus	UBERON:0001875	88.52	gold quality
corpus callosum	UBERON:0002336	88.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.40	gold quality
postcentral gyrus	UBERON:0002581	88.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.36
E-MTAB-6379	no	308.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ARID3B, ATF3, CEBPB, DDIT3, E2F1, E2F3, ELF4, ESR1, ESR2, ETS2, EZH2, FOSL1, FOXC1, FOXM1, FOXO3, GATA6, GCM1, HES1, HSF2, IRF1, IRF6, JUN, JUNB, JUND, KAT7, KLF4, KLF9, MYC, NFATC1, NFATC2, NFE2L2, NFKBIA, NR0B2, NR2C2, RELA, SP1, SP3, SSRP1, STAT3

miRNA regulators (miRDB)

322 targeting MAPK8, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559

Literature-anchored findings (GeneRIF, showing 40)

• Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins (PMID:11912216)
• Results show that the N-CoR-HDAC3 complex inhibits JNK activation through the associated GPS2 subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP-1 function. (PMID:11931768)
• These data strongly suggest that in TNF-induced apoptosis, Hsp72 specifically interferes with the Bid-dependent apoptotic pathway via inhibition of JNK. (PMID:11971973)
• novel role for the I kappa B kinase complex-associated protein (IKAP) in the regulation of activation of the mammalian stress response via the c-Jun N-terminal kinase (JNK)-signaling pathway (PMID:12058026)
• role in stabilizing p21(Cip1) by phosphorylation (PMID:12058028)
• the NOx-induced cell proliferation via activation of JNK1 might contribute to lung tissue damage caused by NOx (PMID:12079429)
• Galpha13 can induce ppET-1 gene expression through a JNK-mediated pathway. (PMID:12135322)
• Elevated JNK activation contributes to the pathogenesis of human brain tumors (PMID:12140754)
• Jun kinase modulates tumor necrosis factor-dependent apoptosis in liver cells (PMID:12143039)
• Unimpaired activation of c-Jun NH2-terminal kinase (JNK) 1 upon CD40 stimulation in B cells of patients with X-linked agammaglobulinemia. (PMID:12148599)
• description of the signaling of JNK and p38 MAPK in apoptosis after stimulation by antioxidants (PMID:12206715)
• TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB. (PMID:12296995)
• JNK has isoform-selective gene regulation and distinct JNK isoforms have a role in specific cellular responses (PMID:12354774)
• Relationship of Mcl-1 isoforms, ratio p21WAF1/cyclin A and this protein phosphorylation to apoptosis in human breast carcinomas. (PMID:12359245)
• Psoriatic epidermis shows selective activation of ERK and JNK, which might be related to hyperproliferation and abnormal differentiation of psoriatic epidermis. (PMID:12413764)
• JNK activation is predominantly involved in the induction of CD44 expression in monocytic cells via lipopolysaccharide-mediated signaling. (PMID:12421945)
• JNK-1 and p38 play a role in apoptosis induced by capsaicin in H-ras-transformed tumor cells (PMID:12478662)
• phosphorylation of JNK1 and WOX1 is necessary for their physical interaction and functional antagonism (PMID:12514174)
• JNK is required for growth of prostate carcinoma cells in vitro and in vivo (PMID:12538493)
• Western blot demonstrated that phosphorylation of JNK was induced only by TPA during 30 min to 1 h. (PMID:12592382)
• Data suggest that epidermal growth factor (EGF) stimulated c-Jun N-terminal kinase phosphorylation of c-Jun is uncoupled from protein kinase D suppression in cancer cells. (PMID:12646240)
• JNK1 has a role in the synergistic effect of TRAIL combined with DNA damage by mediating signals independent of p53 leading to apoptosis (PMID:12707267)
• Results suggest that tissue or plasma fibronectin may modulate the intestinal epithelial response to repetitive deformation through inhibted activation of p38 and jun kinases. (PMID:12810082)
• c-Jun N-terminal kinase plays a negative role in the production of IL-12 from human macrophages stimulated by lipopolysaccharide. (PMID:12847227)
• Data show that inhibition of arachidonate 5-lipoxygenase induces rapid activation of c-Jun N-terminal kinase (JNK) in human prostate cancer cells which is prevented by the 5-lipoxygenase metabolite, 5(S)-HETE. (PMID:12859962)
• Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. (PMID:12878610)
• adipose cytokines and JNK are key mediators between obesity and hormone-resistant prostate cancer (PMID:12902351)
• Threonine 668 within the Amyloid beta protein precursor intracellular domain is indeed phosphorylated by JNK1; although JIP-1 can facilitate this phosphorylation, it is not required for this process. (PMID:12917434)
• Findings strongly suggest that the JNK/AP-1 transcription factor signaling pathway has little or no impact on the generation of inflammatory mediators in neutrophils. (PMID:14500675)
• late but not early JNK1 activation is associated with the induction of apoptosis (PMID:14514687)
• Results show that tumor necrosis factor alpha-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving c-Jun N-terminal kinase, Bid, and Smac/DIABLO. (PMID:14532003)
• c-Jun N-terminal kinase activation in T cell receptor signaling is mediated by SH3 domain-containing adaptor HIP-55 (PMID:14557276)
• JNK inhibition with SP600125 also blocked binding of Sp1 to the DR5/TRAIL-R2 promoter. (PMID:14561739)
• Fas-induced cell death and JNK activation are sensitive to Fas stimulation in cell lines carrying undetectable level of c-FLIP(L). (PMID:14637155)
• Stress-activated protein kinase 1 is involved in the control of monocyte chemoattractant protein-1-induced migration of MonoMac6 cells. (PMID:14688370)
• JNK activation is important for lipopolysacchairde-induced MCP-1 expression but not for TNF-alpha or IL-8 expression (PMID:14699155)
• data support an essential role for JNK signaling in the induction of growth inhibition and apoptosis by As(2)O(3) (PMID:14701702)
• activation of JNK is important for the induction of apoptosis following stresses that function at different cell cycle phases, and that basal JNK activity is necessary to promote proliferation and maintain diploidy in breast cancer cells (PMID:14724588)
• Calcium signaling in ovarian surface epithelial cells not only induces telomerase activity via JNK but also activates Pyk2. (PMID:14729602)
• JNK regulates the expression of HIPK3 in prostate cancer cells, which leads to increased resistance to Fas receptor-mediated apoptosis by reducing the interaction between FADD and caspase-8 (PMID:14766760)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk8b	ENSDARG00000009870
danio_rerio	mapk8a	ENSDARG00000031888
mus_musculus	Mapk8	ENSMUSG00000021936
rattus_norvegicus	Mapk8	ENSRNOG00000020155
drosophila_melanogaster	nmo	FBGN0011817
drosophila_melanogaster	CG8565	FBGN0030697
drosophila_melanogaster	SRPK	FBGN0286813
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00003048
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
caenorhabditis_elegans		WBGENE00004980
caenorhabditis_elegans	gskl-2	WBGENE00007977
caenorhabditis_elegans	Y106G6E.1	WBGENE00013705

Paralogs (19): MAPK9 (ENSG00000050748), MAPK6 (ENSG00000069956), MOK (ENSG00000080823), NLK (ENSG00000087095), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Mitogen-activated protein kinase 8 — P45983 (reviewed: P45983)

Alternative names: JNK-46, Stress-activated protein kinase 1c, Stress-activated protein kinase JNK1, c-Jun N-terminal kinase 1

All UniProt accessions (5): P45983, A0A3B3IRW7, A1L4K2, C9J762, C9JWQ4

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the regulation of the circadian clock. Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity. Phosphorylates POU5F1, which results in the inhibition of POU5F1’s transcriptional activity and enhances its proteasomal degradation. Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1. In neurons, phosphorylates SYT4 which captures neuronal dense core vesicles at synapses. Phosphorylates EIF4ENIF1/4-ET in response to oxidative stress, promoting P-body assembly. Phosphorylates SIRT6 in response to oxidative stress, stimulating its mono-ADP-ribosyltransferase activity. Phosphorylates NLRP3, promoting assembly of the NLRP3 inflammasome. Phosphorylates ALKBH5 in response to reactive oxygen species (ROS), promoting ALKBH5 sumoylation and inactivation. JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.

Subunit / interactions. Forms a complex with MAPK8IP1 and ARHGEF28. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8IP1/JIP1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK9/JNK2. Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway. Interacts with TP53 and WWOX. Interacts with JAMP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs under both normal growth conditions and immediately upon heat shock. Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells. Interacts with NFATC4. Interacts with MECOM; regulates JNK signaling. Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates. Interacts with GRIPAP1. Interacts with POU5F1; phosphorylates POU5F1 at ‘Ser-355’. Interacts with STMN2, STMN3 and STMN4. Interacts with HSF4.

Subcellular location. Cytoplasm. Nucleus. Synapse.

Post-translational modifications. Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Phosphorylated by TAOK2. May be phosphorylated at Thr-183 and Tyr-185 by MAP3K1/MEKK1. Phosphorylated form is more concentrated at synapses than none-phosphorylated.

Activity regulation. Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by SERPINB3.

Domain organisation. The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

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

Isoforms (5)

UniProt ID	Names	Canonical?
P45983-1	2, JNK1-alpha-2	yes
P45983-2	1, JNK1-alpha-1
P45983-3	3, JNK1-beta-1
P45983-4	4, JNK1-beta-2
P45983-5	5

RefSeq proteins (17): NP_001265476, NP_001265477, NP_001310231, NP_001310249, NP_001310250, NP_001310251, NP_001310252, NP_001310253, NP_001310254, NP_001310255, NP_001310256, NP_001310257, NP_001310258, NP_001310259, NP_001310260, NP_620634, NP_620637 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003527	MAP_kinase_CS	Conserved_site
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR008351	MAPK_JNK	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR050117	MAPK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.24 — mitogen-activated protein kinase (BRENDA: 48 organisms, 305 substrates, 720 inhibitors, 27 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.048–0.096	4
ATF2DELTA109	0.002–0.02	2
EGF RECEPTOR PEPTIDE	0.656–2.8	2
ERKSUB	0.127–1.2	2
MEK1ERK	0.0037–0.065	2
MEK2ERK	0.0056–0.03	2
ELKERK	0.0044	1
ERKMEK1	0.344	1
ERKMEK2	0.388	1
ERKSTE7	0.173	1
PROTEIN ATF2	0.0019	1
SCRAMMMEK2	0.096	1
STE7ERK	0.0006	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 (66 total): helix 20, strand 16, modified residue 7, splice variant 4, turn 4, sequence variant 3, mutagenesis site 3, compositionally biased region 2, binding site 2, chain 1, domain 1, region of interest 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2XRW	X-RAY DIFFRACTION	1.33
4QTD	X-RAY DIFFRACTION	1.5
8R5E	X-RAY DIFFRACTION	1.7
3ELJ	X-RAY DIFFRACTION	1.8
4AWI	X-RAY DIFFRACTION	1.91
4L7F	X-RAY DIFFRACTION	1.95
3PZE	X-RAY DIFFRACTION	2
8X5M	X-RAY DIFFRACTION	2
4HYU	X-RAY DIFFRACTION	2.15
4E73	X-RAY DIFFRACTION	2.27
4IZY	X-RAY DIFFRACTION	2.3
4UX9	X-RAY DIFFRACTION	2.34
1UKH	X-RAY DIFFRACTION	2.35
9FT9	X-RAY DIFFRACTION	2.35
4YR8	X-RAY DIFFRACTION	2.4
8PTA	X-RAY DIFFRACTION	2.41
4HYS	X-RAY DIFFRACTION	2.42
4G1W	X-RAY DIFFRACTION	2.45
2XS0	X-RAY DIFFRACTION	2.6
3VUM	X-RAY DIFFRACTION	2.69
6ZR5	X-RAY DIFFRACTION	2.7
1UKI	X-RAY DIFFRACTION	2.7
3O2M	X-RAY DIFFRACTION	2.7
3V3V	X-RAY DIFFRACTION	2.7
3VUH	X-RAY DIFFRACTION	2.7
6F5E	X-RAY DIFFRACTION	2.7
8PT9	X-RAY DIFFRACTION	2.7
8PT8	X-RAY DIFFRACTION	2.78
3VUI	X-RAY DIFFRACTION	2.8
3VUL	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45983-F1	83.75	0.66

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): 151 (proton acceptor)

Ligand- & substrate-binding residues (2): 32–40; 55

Post-translational modifications (7): 183, 185, 377, 377, 377, 301, 116

Mutagenesis-validated functional residues (3):

Position	Phenotype
55	abolished protein kinase activity.
183	phosphorylation blocked.
185	phosphorylation blocked.

Function

Pathways and Gene Ontology

Reactome pathways

58 pathways

ID	Pathway
R-HSA-111446	Activation of BIM and translocation to mitochondria
R-HSA-139910	Activation of BMF and translocation to mitochondria
R-HSA-193648	NRAGE signals death through JNK
R-HSA-205043	NRIF signals cell death from the nucleus
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-450341	Activation of the AP-1 family of transcription factors
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-9007892	Interleukin-38 signaling
R-HSA-9673324	WNT5:FZD7-mediated leishmania damping
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-1280215	Cytokine Signaling in 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
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 641 (showing top): PID_BCR_5PATHWAY, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PROTEIN_BINDING, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, BIOCARTA_MAL_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, BIOCARTA_ATM_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, HOFMANN_CELL_LYMPHOMA_UP, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (40): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), autophagy (GO:0006914), response to oxidative stress (GO:0006979), integrin-mediated signaling pathway (GO:0007229), JNK cascade (GO:0007254), JUN phosphorylation (GO:0007258), response to UV (GO:0009411), response to mechanical stimulus (GO:0009612), negative regulation of autophagy (GO:0010507), positive regulation of gene expression (GO:0010628), regulation of macroautophagy (GO:0016241), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), positive regulation of cyclase activity (GO:0031281), positive regulation of cell killing (GO:0031343), negative regulation of protein binding (GO:0032091), regulation of protein localization (GO:0032880), cellular response to amino acid starvation (GO:0034198), cellular response to oxidative stress (GO:0034599), cellular response to reactive oxygen species (GO:0034614), Fc-epsilon receptor signaling pathway (GO:0038095), regulation of circadian rhythm (GO:0042752), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), rhythmic process (GO:0048511), positive regulation of protein metabolic process (GO:0051247), stress-activated MAPK cascade (GO:0051403), cellular response to lipopolysaccharide (GO:0071222), cellular response to mechanical stimulus (GO:0071260), cellular senescence (GO:0090398), energy homeostasis (GO:0097009), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), positive regulation of protein localization to mitochondrion (GO:1903749), double-strand break repair (GO:0006302), regulation of mRNA stability (GO:0043488), NLRP3 inflammasome complex assembly (GO:0044546), mRNA destabilization (GO:0061157), protein poly-ADP-ribosylation (GO:0070212), protein localization to site of double-strand break (GO:1990166)

GO Molecular Function (15): protein serine/threonine kinase activity (GO:0004674), JUN kinase activity (GO:0004705), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein phosphatase binding (GO:0019903), histone deacetylase regulator activity (GO:0035033), histone deacetylase binding (GO:0042826), protein serine kinase activity (GO:0106310), protein serine/threonine kinase binding (GO:0120283), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), MAP kinase activity (GO:0004707), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), axon (GO:0030424), synapse (GO:0045202), basal dendrite (GO:0097441)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Activation of BH3-only proteins	2
Cell death signalling via NRAGE, NRIF and NADE	2
Cellular Senescence	1
Fc epsilon receptor (FCERI) signaling	1
MAP kinase activation	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
DNA Double Strand Break Response	1
Interleukin-1 family signaling	1
Killing mechanisms	1
Signaling by ALK in cancer	1
Programmed Cell Death	1
Apoptosis	1
Intrinsic Pathway for Apoptosis	1
Immune System	1
Toll-like Receptor Cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein phosphorylation	3
cellular anatomical structure	3
MAPK cascade	2
JNK cascade	2
regulation of autophagy	2
protein binding	2
protein kinase activity	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
response to stress	1
cell surface receptor signaling pathway	1
response to light stimulus	1
response to external stimulus	1
response to abiotic stimulus	1
autophagy	1
negative regulation of catabolic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
macroautophagy	1
peptidyl-serine modification	1
peptidyl-threonine modification	1
cyclase activity	1
positive regulation of catalytic activity	1
cell killing	1
regulation of cell killing	1
positive regulation of cellular process	1
regulation of protein binding	1
negative regulation of binding	1
intracellular protein localization	1
regulation of localization	1
cellular response to starvation	1
response to amino acid starvation	1
response to oxidative stress	1
cellular response to chemical stress	1
MAP kinase activity	1

Protein interactions and networks

STRING

5312 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK8	MAPK8IP1	Q9UQF2	993
MAPK8	JUN	P05412	978
MAPK8	IL6	P05231	938
MAPK8	CASP3	P42574	923
MAPK8	MAP2K4	P45985	892
MAPK8	TNF	P01375	890
MAPK8	GSTP1	P09211	875
MAPK8	DUSP1	P28562	874
MAPK8	NFKB1	P19838	870
MAPK8	TP53	P04637	861
MAPK8	FOS	P01100	850
MAPK8	JUND	P17535	848
MAPK8	IL1B	P01584	845
MAPK8	CASP8	Q14790	810
MAPK8	SMAD4	Q13485	799

IntAct

145 interactions, top by confidence:

A	B	Type	Score
RPTOR	MTOR	psi-mi:“MI:0914”(association)	0.980
MAPK8	JUN	psi-mi:“MI:0407”(direct interaction)	0.850
JUN	MAPK8	psi-mi:“MI:0217”(phosphorylation reaction)	0.850
MAPK8	JUN	psi-mi:“MI:0217”(phosphorylation reaction)	0.850
DUSP4	MAPK1	psi-mi:“MI:0915”(physical association)	0.810
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
MAPK8IP1	MAPK8	psi-mi:“MI:0914”(association)	0.770
CDK19	MED19	psi-mi:“MI:0914”(association)	0.770
MAPK9	MAPK8	psi-mi:“MI:0914”(association)	0.770
MAPK9	MAPK8	psi-mi:“MI:0915”(physical association)	0.770
MAPK8	MAPK8IP1	psi-mi:“MI:0915”(physical association)	0.770
MAP2K4	MAPK8	psi-mi:“MI:0407”(direct interaction)	0.760
MAPK8	WDR62	psi-mi:“MI:0914”(association)	0.730
MAPK8IP1	MAP3K7	psi-mi:“MI:0914”(association)	0.720
MAP3K7	MAP2K7	psi-mi:“MI:0915”(physical association)	0.670
DUSP8	MAPK8	psi-mi:“MI:0914”(association)	0.660
MAPK8	DUSP8	psi-mi:“MI:0915”(physical association)	0.660
MAPK8IP1	MAP2K7	psi-mi:“MI:0914”(association)	0.620
PIK3R1	MAPK8	psi-mi:“MI:0915”(physical association)	0.620
EGFR	MAPK8	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (527): JUN (Biochemical Activity), YWHAZ (Biochemical Activity), MAPK8 (Affinity Capture-Western), ATF2 (Biochemical Activity), SP1 (Biochemical Activity), EP300 (Biochemical Activity), MAPK8IP1 (Affinity Capture-Western), MAPK8 (Two-hybrid), AKT1 (Biochemical Activity), CCT2 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), CCT8 (Affinity Capture-MS), NUP98 (Affinity Capture-MS)

ESM2 similar proteins: A2ZAB5, B6F107, O42099, O54833, O64812, O64816, O64817, O76484, P08181, P0C5D6, P18334, P19139, P19784, P20427, P21868, P21869, P28020, P28523, P28547, P33674, P40231, P43291, P43292, P45983, P49137, P49185, P68399, P68400, P79996, P92208, Q02720, Q08466, Q08467, Q3UMW7, Q4U925, Q5N942, Q60737, Q6ZI44, Q7XKA8, Q7XQP4

Diamond homologs: A3LUB9, B0XPE4, C0LGF4, C0LGL9, D2HHP1, G0RBE3, O64784, O65530, O94537, P32361, P39073, P45983, P45984, P49185, P49186, P49187, P49336, P53779, P79996, P92208, Q09499, Q17IE8, Q1EBK0, Q1XHL7, Q336M2, Q38SD2, Q3UHC2, Q4P9T2, Q4WJJ0, Q4WKP8, Q54IE8, Q557G1, Q559A2, Q55DJ8, Q55GJ2, Q61831, Q66KH9, Q6CCB0, Q6P3N6, Q751F5

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
TRIM27	up-regulates	MAPK8
MAPK8	“down-regulates activity”	ATN1	phosphorylation
MAPK8	“up-regulates activity”	HNRNPK	phosphorylation
MAPK8	up-regulates	HNRNPK	phosphorylation
MAPK8	“up-regulates quantity by stabilization”	TP53	phosphorylation
anthra[1,9-cd]pyrazol-6(2H)-one	down-regulates	MAPK8	“chemical inhibition”
MAPK8	up-regulates	KRT8	phosphorylation
MAPK8	up-regulates	TP53	phosphorylation
DUSP19	down-regulates	MAPK8	dephosphorylation
MAPK8	up-regulates	APP	phosphorylation
MAPK8	down-regulates	NFATC2	phosphorylation
MAPK8	down-regulates	NFATC3	phosphorylation
MAPK8	down-regulates	IRS1	phosphorylation
MAPK8	down-regulates	BAD	phosphorylation
MAPK8	up-regulates	APLP2	phosphorylation
ROCK1	“up-regulates activity”	MAPK8	phosphorylation
MAPK8	up-regulates	BAX
MAPK8	down-regulates	SFN	phosphorylation
MAPK8	down-regulates	YWHAZ	phosphorylation
MAPK8IP1	down-regulates	MAPK8	binding
MAPK8	down-regulates	LAT	phosphorylation
MAPK8	up-regulates	FOXO4	phosphorylation
MAPK8	down-regulates	YWHAB	phosphorylation
MAPK8	up-regulates	MAPK8IP3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	5	29.8×	2e-05
MAP kinase activation	7	24.8×	1e-06
FCERI mediated MAPK activation	6	23.9×	7e-06
Fc epsilon receptor (FCERI) signaling	7	21.9×	2e-06
Interleukin-17 signaling	7	20.4×	2e-06
Toll Like Receptor 10 (TLR10) Cascade	8	19.8×	1e-06
Toll Like Receptor 5 (TLR5) Cascade	8	19.8×	1e-06
MyD88 cascade initiated on plasma membrane	8	18.8×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
Fc-epsilon receptor signaling pathway	6	40.7×	4e-06
stress-activated MAPK cascade	5	32.5×	1e-04
JNK cascade	10	25.2×	8e-09
extrinsic apoptotic signaling pathway via death domain receptors	6	22.3×	9e-05
positive regulation of stress fiber assembly	5	14.4×	2e-03
outflow tract morphogenesis	5	14.2×	2e-03
negative regulation of autophagy	5	12.0×	4e-03
positive regulation of JNK cascade	7	10.6×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	3
Benign	18

Top pathogenic / likely-pathogenic (0)

SpliceAI

2930 predictions. Top by Δscore:

Variant	Effect	Δscore
10:48306820:GG:G	donor_gain	1.0000
10:48306821:GG:G	donor_gain	1.0000
10:48401603:A:AG	acceptor_gain	1.0000
10:48401604:T:G	acceptor_gain	1.0000
10:48401608:GCAGC:G	acceptor_loss	1.0000
10:48401610:A:AG	acceptor_gain	1.0000
10:48401610:AGC:A	acceptor_loss	1.0000
10:48401611:G:A	acceptor_loss	1.0000
10:48401611:G:GA	acceptor_gain	1.0000
10:48401611:GC:G	acceptor_gain	1.0000
10:48401611:GCT:G	acceptor_gain	1.0000
10:48401611:GCTT:G	acceptor_gain	1.0000
10:48401611:GCTTC:G	acceptor_gain	1.0000
10:48401778:GTATG:G	donor_gain	1.0000
10:48401783:G:GG	donor_gain	1.0000
10:48404850:A:AG	acceptor_gain	1.0000
10:48404850:AGC:A	acceptor_gain	1.0000
10:48404851:G:GA	acceptor_gain	1.0000
10:48404851:GC:G	acceptor_gain	1.0000
10:48404851:GCG:G	acceptor_gain	1.0000
10:48404851:GCGC:G	acceptor_gain	1.0000
10:48404851:GCGCA:G	acceptor_gain	1.0000
10:48404977:AAAAT:A	donor_gain	1.0000
10:48404978:AAAT:A	donor_gain	1.0000
10:48404979:AAT:A	donor_gain	1.0000
10:48404979:AATG:A	donor_loss	1.0000
10:48404980:AT:A	donor_gain	1.0000
10:48404981:TGTA:T	donor_loss	1.0000
10:48404982:G:GG	donor_gain	1.0000
10:48404982:G:T	donor_loss	1.0000

AlphaMissense

2825 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:48401725:T:A	V22D	1.000
10:48401757:G:C	G33R	1.000
10:48401763:G:A	G35R	1.000
10:48401763:G:C	G35R	1.000
10:48401764:G:A	G35E	1.000
10:48401767:C:A	A36D	1.000
10:48401772:G:A	G38R	1.000
10:48401772:G:C	G38R	1.000
10:48401773:G:A	G38E	1.000
10:48401773:G:T	G38V	1.000
10:48401779:T:A	V40E	1.000
10:48404856:G:C	A43P	1.000
10:48404857:C:A	A43D	1.000
10:48404884:T:A	V52D	1.000
10:48404887:C:A	A53E	1.000
10:48404890:T:A	I54N	1.000
10:48404892:A:C	K55Q	1.000
10:48404892:A:G	K55E	1.000
10:48404894:G:C	K55N	1.000
10:48404894:G:T	K55N	1.000
10:48404908:C:A	P60Q	1.000
10:48404908:C:G	P60R	1.000
10:48404910:T:C	F61L	1.000
10:48404911:T:C	F61S	1.000
10:48404912:T:A	F61L	1.000
10:48404912:T:G	F61L	1.000
10:48404928:G:C	A67P	1.000
10:48404929:C:A	A67D	1.000
10:48404933:G:C	K68N	1.000
10:48404933:G:T	K68N	1.000

dbSNP variants (sampled 300 via entrez): RS1000001859 (10:48348954 A>G), RS1000005083 (10:48399675 C>T), RS1000010300 (10:48436574 C>A), RS1000022106 (10:48314098 T>C), RS1000051825 (10:48314361 A>G), RS1000075306 (10:48354012 A>G), RS1000075748 (10:48393096 A>G), RS1000086203 (10:48320333 G>T), RS1000088478 (10:48388073 AG>A), RS1000107744 (10:48416530 A>G,T), RS1000128286 (10:48310060 A>G), RS1000224505 (10:48416234 A>G), RS1000260273 (10:48336281 A>C), RS1000277046 (10:48416018 G>A), RS1000323432 (10:48375419 G>A,T)

Disease associations

OMIM: gene MIM:601158 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary skin disorder	Moderate	Autosomal dominant

Mondo (1): hereditary skin disorder (MONDO:0100118)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003518_9	Daytime sleep phenotypes	4.000000e-06
GCST009731_30	Blood protein levels in cardiovascular risk	3.000000e-06
GCST010002_287	Refractive error	2.000000e-49
GCST012222_5	Opioid dependence (time to event)	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D012873	Skin Diseases, Genetic	C16.320.850; C17.800.827

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096667 (PROTEIN FAMILY), CHEMBL2276 (SINGLE PROTEIN), CHEMBL4296098 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

50 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 292,796 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2103830	FOSTAMATINIB	4	3,841
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL941	IMATINIB	4	111,611
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1950289	TANZISERTIB	2	419
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1090089	PAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL1614713	CC-401	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1944698	ZOTIRACICLIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL2029988	CEP-32496	2
CHEMBL3545213	BENTAMAPIMOD	2
CHEMBL363648	TAK-715	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — JNK subfamily

Most potent curated ligand interactions (14 total), top 14:

Ligand	Action	Affinity	Parameter
JNK inhibitor VIII	Inhibition	8.7	pKi
JNK-IN-8	Inhibition	8.33	pIC50
compound 20 [PMID: 30998356]	Inhibition	7.49	pIC50
SP600125	Inhibition	7.4	pIC50
tanzisertib	Inhibition	7.21	pIC50
BOS172722	Inhibition	7.04	pIC50
compound 35 [PMID: 23916259]	Inhibition	7.04	pIC50
JNK inhibitor 9l	Inhibition	7.0	pIC50
GNE-3511	Inhibition	6.89	pIC50
pamapimod	Inhibition	6.72	pKd
SU-3327	Inhibition	6.15	pIC50
compound 11 [PMID: 26431428]	Inhibition	6.0	pIC50
YL5084	Inhibition	5.66	pIC50
compound 25c [PMID: 36649216]	Inhibition	5.0	pIC50

Binding affinities (BindingDB)

555 measured of 806 human assays (807 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-{[2-({5-[2-(dimethylamino)acetamido]-2-methoxy-4-methylphenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	0.5 nM
JNK-IN-11	IC50	0.5 nM
JNK-IN-7	IC50	0.75 nM
JNK-IN-5	IC50	0.96 nM
JNK-IN-8	IC50	0.98 nM
1-benzyl-N-[[7-chloro-2-(1,3-oxazol-2-yl)-4-oxo-1-phenylquinolin-3-yl]methyl]-2-oxopyridine-4-carboxamide	IC50	1 nM	US-8501732: Aminomethyl quinolone compounds
2-{[2-({5-[2-(dimethylamino)acetamido]-2-methoxyphenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	1 nM
2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	1 nM
2-fluoro-6-{[2-({5-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	1 nM
2-{[2-({1-[2-(azetidin-1-yl)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	1 nM
2-{[2-({1-[2-(dimethylamino)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	1 nM
2-fluoro-6-{[2-({6-methoxy-1-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	1 nM
Staurosporine	KD	1.7 nM
BMCL19469 Compound 13	IC50	2 nM
2-fluoro-6-{[2-({5-methoxy-1-[2-(methylamino)acetyl]-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	2 nM
2-{[2-({1-[2-(diethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	2 nM
2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide	IC50	2 nM
2-({2-[(1-{2-[ethyl(methyl)amino]acetyl}-5-methoxy-2,3-dihydro-1H-indol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide	IC50	3 nM
[4-[[4-[4-(4-methylsulfonylpiperidin-1-yl)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone	IC50	3.6 nM	US-8536172: Inhibitors of JNK
1-benzyl-N-[[2-(1,3-oxazol-2-yl)-4-oxo-1-phenyl-1,8-naphthyridin-3-yl]methyl]-2-oxopyridine-4-carboxamide	IC50	4 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(4-methylsulfonylbenzoyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	4 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[[4-(1,3-oxazol-5-yl)benzoyl]amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	4 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-fluoro-3-[[(6-morpholin-4-ylpyridine-3-carbonyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	4 nM	US-8501732: Aminomethyl quinolone compounds
JNK3 inhibitor 4	KI	4 nM	US-8563583: Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
4-(5-{[(4-Amino-5-cyano-6-ethoxy-pyridine-2-carbonyl)-amino]-methyl}-pyridin-2-yl)-benzoic acid	IC50	4 nM
2-fluoro-6-{[2-({2-methoxy-5-[4-(propan-2-yl)piperazin-1-yl]phenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	4 nM
2-[(2-{[1-(2-aminoacetyl)-5-methoxy-2,3-dihydro-1H-indol-6-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide	IC50	4 nM
2-fluoro-6-({2-[(5-methoxy-1-{3-[4-(propan-2-yl)piperazin-1-yl]propanoyl}-2,3-dihydro-1H-indol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide	IC50	4 nM
3-[4-[1-[2-(cyclohexylamino)pyrimidin-4-yl]indol-4-yl]piperazin-1-yl]-3-oxopropanenitrile	IC50	4.9 nM	US-8536172: Inhibitors of JNK
methyl 7-chloro-4-oxo-1-phenyl-3-[[[4-(1H-1,2,4-triazol-5-yl)benzoyl]amino]methyl]quinoline-2-carboxylate	IC50	5 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(6-morpholin-4-ylpyridine-3-carbonyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	6 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(4-methoxycarbonylbenzoyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	6 nM	US-8501732: Aminomethyl quinolone compounds
US8937068, 43	IC50	6 nM	US-8937068: Pyridopyrazine derivatives and their use
2-fluoro-6-{[2-({2-methoxy-5-[(1-propylpiperidin-4-yl)oxy]phenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	6 nM
2-({2-[(1-acetyl-5-methoxy-2,3-dihydro-1H-indol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide	IC50	6 nM
2-fluoro-6-{[2-({5-methoxy-1-[3-(morpholin-4-yl)propanoyl]-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide	IC50	6 nM
N-[[7-chloro-2-(1,3-oxazol-2-yl)-4-oxo-1-phenylquinolin-3-yl]methyl]-2-morpholin-4-ylpyridine-4-carboxamide	IC50	7 nM	US-8501732: Aminomethyl quinolone compounds
6-[4-(hydroxymethyl)piperidin-1-yl]-N-[[2-(1,3-oxazol-2-yl)-4-oxo-1-phenyl-1,8-naphthyridin-3-yl]methyl]pyridine-3-carboxamide	IC50	7 nM	US-8501732: Aminomethyl quinolone compounds
methyl 3-[(1,3-benzothiazole-5-carbonylamino)methyl]-7-chloro-4-oxo-1-phenylquinoline-2-carboxylate	IC50	7 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[[4-(1H-imidazol-2-yl)benzoyl]amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	7 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(4-methoxybenzoyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	7 nM	US-8501732: Aminomethyl quinolone compounds
JNK3 inhibitor 3	KI	7 nM	US-8563583: Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
Aminopyrazole inhibitor, 3576	IC50	7 nM
methyl 7-chloro-4-oxo-1-phenyl-3-[[(4-sulfamoylbenzoyl)amino]methyl]quinoline-2-carboxylate	IC50	8 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(2-morpholin-4-yl-1,3-thiazole-5-carbonyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	8 nM	US-8501732: Aminomethyl quinolone compounds
methyl 7-chloro-3-[[(3-methoxybenzoyl)amino]methyl]-4-oxo-1-phenylquinoline-2-carboxylate	IC50	8 nM	US-8501732: Aminomethyl quinolone compounds
2-{[2-({5-[3-(dimethylamino)propoxy]-2-methoxyphenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	8 nM
2-{[2-({1-[3-(dimethylamino)propanoyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluorobenzamide	IC50	8 nM
N-[[7-chloro-2-(1,3-oxazol-2-yl)-4-oxo-1-phenylquinolin-3-yl]methyl]-6-morpholin-4-ylpyridine-3-carboxamide	IC50	9 nM	US-8501732: Aminomethyl quinolone compounds
2-({2-[(3-hydroxyphenyl)amino]pyrimidin-4-yl}amino)benzamide	IC50	9 nM

ChEMBL bioactivities

2378 potent at pChembl≥5 of 2530 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.49	IC50	0.032	nM	CHEMBL4546504
9.85	Kd	0.14	nM	CHEMBL2392833
9.62	IC50	0.24	nM	CHEMBL3220502
9.15	IC50	0.7	nM	CHEMBL1822313
9.12	Kd	0.75	nM	CHEMBL2425628
9.10	IC50	0.8	nM	CHEMBL3393600
9.10	IC50	0.8	nM	CHEMBL6165786
9.05	IC50	0.9	nM	CHEMBL1822313
9.00	IC50	1	nM	CHEMBL3220493
9.00	Ki	1	nM	CHEMBL378627
9.00	IC50	1	nM	CHEMBL3679421
9.00	IC50	1	nM	CHEMBL2216824
9.00	IC50	1	nM	CHEMBL4856984
9.00	IC50	1	nM	CHEMBL4849353
9.00	IC50	1	nM	CHEMBL1822151
9.00	IC50	1	nM	CHEMBL1822152
9.00	IC50	1	nM	CHEMBL1822305
8.89	IC50	1.3	nM	CHEMBL3393608
8.85	IC50	1.4	nM	CHEMBL6141745
8.82	IC50	1.5	nM	CHEMBL3393607
8.82	IC50	1.5	nM	CHEMBL6145686
8.82	Ki	1.5	nM	CHEMBL1822314
8.81	IC50	1.54	nM	CHEMBL3393607
8.74	IC50	1.81	nM	CHEMBL5647005
8.70	Ki	2	nM	CHEMBL210618
8.70	IC50	2	nM	CHEMBL3674700
8.70	IC50	2	nM	CHEMBL437747
8.70	IC50	2	nM	CHEMBL4853125
8.70	IC50	2	nM	CHEMBL4878370
8.70	IC50	2	nM	CHEMBL4864618
8.70	IC50	2	nM	CHEMBL1822146
8.70	IC50	2	nM	CHEMBL1822149
8.70	IC50	2	nM	CHEMBL1822309
8.70	Ki	2	nM	CHEMBL1822314
8.70	Ki	1.995	nM	CHEMBL210618
8.62	IC50	2.4	nM	CHEMBL3674715
8.60	Ki	2.512	nM	CHEMBL1987034
8.57	IC50	2.7	nM	CHEMBL6177556
8.52	IC50	3	nM	CHEMBL2392833
8.52	IC50	3	nM	CHEMBL2392825
8.52	IC50	3	nM	CHEMBL3220495
8.52	Ki	3	nM	CHEMBL210963
8.52	Ki	3	nM	CHEMBL210928
8.52	IC50	3	nM	CHEMBL3674690
8.52	IC50	3	nM	CHEMBL4847078
8.52	IC50	3	nM	CHEMBL4853525
8.52	IC50	3	nM	CHEMBL4862107
8.52	IC50	3	nM	CHEMBL4845965
8.52	IC50	3	nM	CHEMBL6141893
8.52	Ki	3	nM	CHEMBL1094014

PubChem BioAssay actives

1902 with measured affinity, of 5982 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
4-[[5-chloro-4-(4-hydroxy-4-methylcyclohexyl)oxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N,N-dimethyl-3-[(2R)-1,1,1-trifluoropropan-2-yl]oxybenzamide	1551595: Inhibition of recombinant human full length His-tagged JNK1 expressed in baculovirus expression system by Z’-LYTE assay	ic50	<0.0001	uM
4-[[4-[4-(4-methylsulfonylpiperidin-1-yl)indol-1-yl]pyrimidin-2-yl]amino]cyclohexan-1-ol	753651: Binding affinity to JNK1 (unknown origin)	kd	0.0001	uM
2-[[5-chloro-2-[4-(2-oxopyrrolidin-1-yl)anilino]pyrimidin-4-yl]amino]benzamide	1189540: Inhibition of JNK1 (unknown origin) by time-resolved fluorescence assay	ic50	0.0002	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3R)-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-N-[2-[[2-[3-[[4-(1H-indazol-3-yl)benzoyl]amino]propylamino]-2-oxoethyl]amino]-2-oxoethyl]butanediamide	617673: Inhibition of JNK1 using ATF2 substrate by TR-FRET assay	ic50	0.0007	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769512: Binding affinity to JNK1 (unknown origin)	kd	0.0008	uM
2-(4-methoxyphenyl)-N-[6-(1-methylpyrazol-4-yl)isoquinolin-3-yl]acetamide	1189540: Inhibition of JNK1 (unknown origin) by time-resolved fluorescence assay	ic50	0.0008	uM
N-(4-amino-5-cyano-6-propan-2-yloxy-2-pyridinyl)-2-(2,5-dimethoxy-4-methylsulfonylphenyl)acetamide	1797445: Kinase Selectivity Assay from Article 10.1021/jm060199b: “Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.”	ki	0.0010	uM
N-[4-bromo-3-(1-methyl-1,2,4-triazol-3-yl)thiophen-2-yl]-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1-yl)acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0010	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-(7-cyano-2-oxoquinolin-1-yl)acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0010	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-(6-cyano-2-oxoquinolin-1-yl)acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0010	uM
3-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[3-methyl-4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	1469780: Inhibition of JNK1 (unknown origin) after 1 hr	ic50	0.0010	uM
4-[[(1R,3S)-3-hydroxy-3-methylcyclohexyl]amino]-2-[(4-methoxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0010	uM
4-[[(1R,3S)-3-hydroxycycloheptyl]amino]-2-[(4-methoxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0010	uM
2-[[5-chloro-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]benzamide	1189540: Inhibition of JNK1 (unknown origin) by time-resolved fluorescence assay	ic50	0.0010	uM
3-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[4-[[4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino]phenyl]benzamide	1189584: Inhibition of JNK1 (unknown origin) after 1 hr incubation	ic50	0.0013	uM
(2R)-N-[(2R)-1-[[(2R)-1-[[(2R)-6-amino-1-[[(2R)-6-amino-1-[[(2R)-1-[(2-amino-2-oxoethyl)amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[2-[[2-[[(2R)-2-[[(2R)-1-[(2R,3S)-2-[[(2R,3S)-2-[[(2R)-2-[[(2R)-4-amino-2-[[(2R)-2-[[2-[[2-[4-[[4-(1H-indazol-3-yl)benzoyl]amino]butanoylamino]acetyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]acetyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]pentanediamide	616254: Competitive inhibition of JNK1 using ATF2 substrate by Lineweaver-Burk analysis	ki	0.0015	uM
3-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	1189584: Inhibition of JNK1 (unknown origin) after 1 hr incubation	ic50	0.0015	uM
N-[3-[[4-[1-tert-butyl-3-(3-hydroxyphenyl)pyrazol-4-yl]-2-pyridinyl]amino]propyl]-4-methoxybenzenesulfonamide	2141948: Inhibition of human JNK1 in presence of ATP	ic50	0.0018	uM
N-(4-amino-5-cyano-6-ethoxy-2-pyridinyl)-2-(2,5-dimethoxyphenyl)acetamide	1797445: Kinase Selectivity Assay from Article 10.1021/jm060199b: “Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.”	ki	0.0020	uM
N-cyclohexyl-4-[5-(3,4-dichlorophenyl)-2-piperidin-4-yl-3-propylimidazol-4-yl]pyrimidin-2-amine	305143: Inhibition of JNK1	ic50	0.0020	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-[2-oxo-6-(trifluoromethyl)quinolin-1-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0020	uM
N-[4-cyano-3-(1,3-thiazol-4-yl)thiophen-2-yl]-2-[2-oxo-6-(trifluoromethyl)quinolin-1-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0020	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-[2-oxo-6-(trifluoromethoxy)quinolin-1-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0020	uM
4-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-[[4-(2,2,2-trifluoroethoxy)cyclohexyl]amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0020	uM
4-[[(1R,3R)-3-hydroxycyclohexyl]amino]-2-[(4-methoxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0020	uM
4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-2-[(4-methoxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0020	uM
3-(prop-2-enoylamino)-N-[4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	1799705: JNK Kinase Assay from Article 10.1016/j.chembiol.2011.11.010: “Discovery of potent and selective covalent inhibitors of JNK.”	ic50	0.0021	uM
N-(4-amino-5-cyano-6-ethoxy-2-pyridinyl)-2-(2,5-dimethoxy-4-methylsulfonylphenyl)acetamide	1797445: Kinase Selectivity Assay from Article 10.1021/jm060199b: “Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.”	ki	0.0030	uM
N-(4-amino-5-chloro-6-ethoxy-2-pyridinyl)-2-(2,5-dimethoxy-4-methylsulfonylphenyl)acetamide	1797445: Kinase Selectivity Assay from Article 10.1021/jm060199b: “Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.”	ki	0.0030	uM
4-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-[[4-(trideuteriomethoxy)cyclohexyl]amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0030	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-(6,7-difluoro-2-oxoquinolin-1-yl)acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0030	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-[5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0030	uM
4-[[4-[1-benzyl-5-(dimethylamino)pyrazol-4-yl]pyrimidin-2-yl]amino]cyclohexan-1-ol	473195: Inhibition of JNK1	ki	0.0030	uM
N-[4-[[4-[4-(4-methylsulfonylpiperidin-1-yl)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanesulfonamide	753664: Inhibition of human JNK1alpha1 using GST-tagged ATF2 as substrate preincubated for 10 mins prior to substrate addition measured after 30 mins by microplate scintillation counting analysis	ic50	0.0030	uM
4-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-[(4-methoxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0030	uM
2-[[4-(difluoromethoxy)cyclohexyl]amino]-4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0030	uM
4-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-[(4-hydroxycyclohexyl)amino]pyrimidine-5-carboxamide	1782600: Inhibition of JNK1 (unknown origin) assessed as reduction in phosphorylated ULight-labeled 4EBP1 peptide measured after 1 hr by time-resolved fluorescence assay	ic50	0.0030	uM
2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]benzamide	1189540: Inhibition of JNK1 (unknown origin) by time-resolved fluorescence assay	ic50	0.0030	uM
4-[[4-[(6-bromo-3-methoxycarbonyl-1-oxo-4-phenylisoquinolin-2-yl)methyl]phenyl]sulfamoyl]benzoic acid	319311: Inhibition of human JNK1 by radiometric assay	ic50	0.0033	uM
N-[3-[[4-[1-tert-butyl-3-(3-hydroxyphenyl)pyrazol-4-yl]-2-pyridinyl]amino]propyl]-4-fluorobenzenesulfonamide	2141948: Inhibition of human JNK1 in presence of ATP	ic50	0.0035	uM
N-[3-[[4-[1-tert-butyl-3-(3-hydroxyphenyl)pyrazol-4-yl]-2-pyridinyl]amino]propyl]benzenesulfonamide	2141948: Inhibition of human JNK1 in presence of ATP	ic50	0.0037	uM
4-amino-5-chloro-6-ethoxy-N-[(4-methylsulfonylphenyl)methyl]pyridine-2-carboxamide	266836: Inhibition of JNK1	ki	0.0038	uM
4-[5-[[(4-amino-5-cyano-6-ethoxypyridine-2-carbonyl)amino]methyl]-2-pyridinyl]benzoic acid	1797442: ATF-2 Phosphorylation Assay from Article 10.1021/jm060465l: “Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.”	ic50	0.0040	uM
N-[4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-(2-oxo-3,4-dihydroquinolin-1-yl)acetamide	579422: Inhibition of recombinant JNK1 after 60 mins by TR-FRET assay	ic50	0.0040	uM
2-[[5-chloro-2-(4-methoxyphenoxy)pyrimidin-4-yl]amino]benzamide	632487: Inhibition of JNK1 using biotinylated-ATF2 as substrate by HTRF assay	ic50	0.0040	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-[2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0040	uM
N-[4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl]-2-(2-oxo-1,6-naphthyridin-1-yl)acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0040	uM
N-[4-cyano-3-(1,3-oxazol-2-yl)thiophen-2-yl]-2-[2-oxo-6-(trifluoromethyl)quinolin-1-yl]acetamide	617475: Inhibition of recombinant JNK1 using ser73 of c-jun as substrate preincubated for 15 mins measured after 60 mins by TR-FRET assay	ic50	0.0040	uM
2-[4-[[4-[4-(3-methylsulfonylpropoxy)indazol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]propan-2-ol	769542: Inhibition of human JNK1 assessed as inhibition of GST-tagged ATF2 (19 to 96) phosphorylation incubated for 10 mins prior to substrate addition measured after 30 mins by scintillation counting analysis in presence of [gamma-33P]-ATP	ic50	0.0040	uM
2-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]propan-2-ol	769542: Inhibition of human JNK1 assessed as inhibition of GST-tagged ATF2 (19 to 96) phosphorylation incubated for 10 mins prior to substrate addition measured after 30 mins by scintillation counting analysis in presence of [gamma-33P]-ATP	ic50	0.0040	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
pyrazolanthrone	decreases reaction, increases expression, affects cotreatment, decreases activity, increases phosphorylation (+3 more)	43
Acetylcysteine	increases activity, increases phosphorylation, affects cotreatment, increases abundance, decreases phosphorylation (+1 more)	34
Arsenic Trioxide	affects response to substance, decreases reaction, increases phosphorylation, increases activity, affects cotreatment (+6 more)	21
Hydrogen Peroxide	decreases reaction, increases phosphorylation, increases reaction, increases expression, affects reaction (+2 more)	18
Lipopolysaccharides	decreases phosphorylation, increases expression, decreases reaction, increases phosphorylation, increases abundance (+2 more)	16
Cadmium Chloride	increases reaction, increases response to substance, decreases reaction, increases activity, increases phosphorylation (+2 more)	15
sodium arsenite	affects reaction, increases reaction, affects binding, decreases expression, increases expression (+5 more)	13
Doxorubicin	affects reaction, increases response to substance, decreases reaction, affects activity, increases activity (+7 more)	13
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, affects reaction (+2 more)	13
Quercetin	affects cotreatment, increases phosphorylation, decreases reaction, increases expression, increases activity (+2 more)	11
Particulate Matter	increases phosphorylation, increases abundance, affects response to substance, decreases expression, increases reaction (+3 more)	11
Resveratrol	decreases expression, decreases phosphorylation, increases activity, affects reaction, increases expression (+5 more)	8
Anisomycin	decreases reaction, increases phosphorylation, increases activity, increases expression, increases reaction	8
Cisplatin	decreases reaction, increases phosphorylation, decreases phosphorylation, increases activity, affects reaction (+1 more)	8
SB 203580	decreases reaction, increases phosphorylation, increases activity, increases reaction, decreases activity	7
Cadmium	decreases reaction, increases abundance, increases phosphorylation, decreases response to substance	7
Capsaicin	increases secretion, decreases degradation, decreases reaction, increases activity, increases phosphorylation (+1 more)	7
trichostatin A	decreases expression, increases activity, affects expression, decreases reaction, increases phosphorylation (+1 more)	6
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	decreases reaction, increases phosphorylation, increases activity, increases expression, increases reaction	6
Oxygen	increases activity, decreases reaction, increases phosphorylation, affects reaction, increases expression (+1 more)	6
Valproic Acid	decreases expression, increases expression, increases methylation, affects cotreatment	6
deoxynivalenol	affects phosphorylation, affects cotreatment, increases phosphorylation, decreases activity, increases expression (+1 more)	5
Bortezomib	increases response to substance, affects cotreatment, decreases reaction, increases activity, increases phosphorylation (+2 more)	5
Air Pollutants	increases phosphorylation, affects response to substance, decreases expression, affects expression, decreases phosphorylation (+2 more)	5
Curcumin	affects reaction, decreases reaction, increases expression, increases phosphorylation	5
Paraquat	increases expression, decreases reaction, increases phosphorylation, increases activity, affects reaction	5
Rotenone	decreases reaction, increases phosphorylation, increases reaction, increases expression, increases activity	5
Silicon Dioxide	increases phosphorylation, decreases reaction	5
Paclitaxel	increases cleavage, affects binding, decreases reaction, increases activity, affects cotreatment (+4 more)	5
bisphenol A	increases phosphorylation, decreases expression, decreases reaction	4

ChEMBL screening assays

1116 unique, capped per target: 1104 binding, 9 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000440	Binding	Inhibition of human JNK expressed in baculovirus insect cell system	Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. — J Med Chem
CHEMBL853927	Functional	Inhibition of PcJun phosphorylation in HepG2 cells	Aminopyridine carboxamides as c-Jun N-terminal kinase inhibitors: targeting the gatekeeper residue and beyond. — Bioorg Med Chem Lett
CHEMBL4325219	ADMET	Inhibition of human JNK1 at 1 uM relative to control	Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7UM	Ubigene A-549 MAPK8 KO	Cancer cell line	Male
CVCL_D9JQ	Ubigene HEK293 MAPK8 KO	Transformed cell line	Female
CVCL_SW99	HAP1 MAPK8 (-) 1	Cancer cell line	Male
CVCL_SX00	HAP1 MAPK8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06509984	PHASE2	RECRUITING	A 20-Week Study Assessing the Efficacy of Apremilast in Patients with EB Simplex Generalized
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT03269474	Not specified	UNKNOWN	Computational Drug Repurposing for All EBS Cases
NCT03873285	Not specified	UNKNOWN	Method of Genetic Analysis in Genodermatoses
NCT04154839	Not specified	UNKNOWN	Epidemiological Survey and Genetic Analysis of AD Patients in Hong Kong