MAPK11

Summary

MAPK11 (mitogen-activated protein kinase 11, HGNC:6873) is a protein-coding gene on chromosome 22q13.33, encoding Mitogen-activated protein kinase 11 (Q15759). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

This gene encodes a member of a family of protein kinases that are involved in the integration of biochemical signals for a wide variety of cellular processes, including cell proliferation, differentiation, transcriptional regulation, and development. The encoded protein can be activated by proinflammatory cytokines and environmental stresses through phosphorylation by mitogen activated protein kinase kinases (MKKs). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5600 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 43 total — 1 pathogenic
• Druggable target: yes — 33 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002751

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6873
Approved symbol	MAPK11
Name	mitogen-activated protein kinase 11
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	p38-2, p38Beta, SAPK2
Ensembl gene	ENSG00000185386
Ensembl biotype	protein_coding
OMIM	602898
Entrez	5600

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000330651, ENST00000395764, ENST00000417877, ENST00000495277, ENST00000880441, ENST00000880442

RefSeq mRNA: 1 — MANE Select: NM_002751 NM_002751

CCDS: CCDS14090

Canonical transcript exons

ENST00000330651 — 12 exons

Exon	Start	End
ENSE00000657641	50267569	50267627
ENSE00000878857	50267257	50267286
ENSE00001641435	50263713	50265027
ENSE00003470895	50266934	50267048
ENSE00003474709	50265582	50265660
ENSE00003487715	50266540	50266611
ENSE00003496825	50267371	50267482
ENSE00003565463	50267820	50267949
ENSE00003631884	50266226	50266305
ENSE00003634258	50265321	50265494
ENSE00003675628	50267127	50267174
ENSE00003850189	50270177	50270380

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 95.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.8775 / max 25.5849, expressed in 1219 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194718	2.3985	1107
194719	0.4790	267

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	95.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.79	gold quality
cerebellar hemisphere	UBERON:0002245	94.02	gold quality
cerebellar cortex	UBERON:0002129	93.77	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.65	gold quality
middle temporal gyrus	UBERON:0002771	93.45	gold quality
cingulate cortex	UBERON:0003027	93.38	gold quality
anterior cingulate cortex	UBERON:0009835	93.35	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.52	gold quality
apex of heart	UBERON:0002098	92.25	gold quality
cerebellum	UBERON:0002037	92.12	gold quality
cortical plate	UBERON:0005343	91.97	gold quality
caudate nucleus	UBERON:0001873	91.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.63	silver quality
putamen	UBERON:0001874	91.48	gold quality
nucleus accumbens	UBERON:0001882	90.74	gold quality
adenohypophysis	UBERON:0002196	90.66	gold quality
amygdala	UBERON:0001876	90.37	gold quality
primary visual cortex	UBERON:0002436	89.74	gold quality
pituitary gland	UBERON:0000007	89.26	gold quality
ganglionic eminence	UBERON:0004023	89.21	gold quality
omental fat pad	UBERON:0010414	89.09	gold quality
peritoneum	UBERON:0002358	89.05	gold quality
temporal lobe	UBERON:0001871	88.80	gold quality
telencephalon	UBERON:0001893	88.77	gold quality
endothelial cell	CL:0000115	88.73	silver quality
adipose tissue of abdominal region	UBERON:0007808	88.64	gold quality
cerebral cortex	UBERON:0000956	88.63	gold quality
forebrain	UBERON:0001890	88.42	gold quality
brain	UBERON:0000955	88.27	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.49

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
HBA1	Activation
HBB	Activation
IL12B	Activation
LGALS9	Activation

Upstream regulators (CollecTRI, top): IRF6, ZBTB7A

miRNA regulators (miRDB)

27 targeting MAPK11, 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-8485	100.00	77.57	4731
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-6811-5P	97.98	64.96	848
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-4298	97.26	66.59	765
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Literature-anchored findings (GeneRIF, showing 40)

• p38 MAP Kinase suppresses the function of Mirk as a transcriptional activator only when cells are proliferating (PMID:12384504)
• the p38MAPK activation-Bax expression pathway might be involved in apoptosis induced by oxidative stress (PMID:12510156)
• Neurotoxicity of pneumolysin depends on activation of p38 mitogen-activated protein kinase. (PMID:12586546)
• activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway (PMID:14522966)
• Activities of aPKC (P<0.05) and ERK 1/2 (P=0.06), but not phosphorylation of P38 MAPK, were higher in trained than in sedentary subjects at rest. (PMID:14651992)
• SAPK2/p38 intervenes in the control of MonoMac6 cell migration induced by monocyte chemoattractant protein-1. (PMID:14688370)
• phosphorylation of Y1214 on VEGFR2 is required to trigger the sequential activation of Cdc42 and SAPK2/p38 and to drive the SAPK2/p38-mediated actin remodeling in stress fibers in endothelial cells exposed to VEGF (PMID:14724572)
• These results suggest that bFGF can negatively modulate p38 and positively modulate ERK1/2 to antagonize activin A-mediated growth inhibition and Hb synthesis in K562 cells. (PMID:15249224)
• SAPK2/p38 mitogen-activated protein kinase is inhibited by PML in tumor cells (PMID:15273249)
• cholesterol depletion alters involucrin gene expression through activation of p38alpha/beta. (PMID:15304097)
• p38SAPK might be involved in the regulation of cyclin D3 levels and suggest that this mechanism is involved in the maturation of precursor T-cells (PMID:15326477)
• p38alpha and -beta mediate UV-induced, AP-1-mediated, c-Fos phosphorylation (PMID:15708845)
• p38 phosphorylation occurred in response to attack by Staphylococcus aureus alpha-toxin and streptolysin O, commencing within minutes after toxin treatment and waning after several hours. (PMID:16643845)
• The authors characterized the multisite phosphorylation of the ATF7 activation domain and identified one of the involved kinase, p38beta2 mitogen-activated protein kinase. (PMID:18950637)
• genistein protects human vascular endothelial cells against tumor necrosis factor-alpha-induced apoptosis through the p38beta mitogen-activated protein kinase (PMID:19082897)
• Specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury. (PMID:19706373)
• results demonstrate that IFN-alpha can regulate growth inhibition of Jurkat cells through p38alpha and p38beta (PMID:20053787)
• These results demonstrate that activin A induces erythroid differentiation of K562 cells through activation of MKK6-p38alpha/p38beta pathway and follistatin inhibits those effects. (PMID:20162623)
• show that p38 MAP kinase directly activates TACE and effects shedding in response to growth factors and Erk MAP kinase activation. (PMID:20188673)
• p38alpha/p38beta and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production (PMID:20378550)
• Overexpression of p38beta or Rac1 significantly enhanced (1.9- and 3.9-fold, respectively), the tRA-stimulated NIS expression in MCF-7 cells. (PMID:22157753)
• Thus, in endothelial cells p38alpha mediates apoptotic signaling, whereas p38beta and p38gamma transduce survival signaling (PMID:22522454)
• Study identifies Hsp27 as a novel target of ILK-p38beta signaling complexes, playing a key role in bladder cancer cell migration. (PMID:23435415)
• inhibition of the SOCE downstream target CaM kinase kinase beta (CaMKKbeta) or knockdown of AMPKalpha1 suppressed PAR-1-mediated phosphorylation of p38beta and hence STIM1. (PMID:23625915)
• p38beta is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. (PMID:23807508)
• Differential roles for p38alpha and p38beta in the HGF-induced expression of key osteogenic markers. (PMID:24673557)
• study identified the structural motif responsible for the unique autophosphorylation capability of p38beta and the motif inhibiting this activity in living cells (PMID:25006254)
• Data show that the p38 MAPK (p38) isoform (p38beta) mitogen-activated protein kinase 11 (MAPK11) is expressed in breast cancer cell. (PMID:25066918)
• The MAPK11 gene was variably methylated in monozygotic twins discordant for depressive disorder. (PMID:25918994)
• These findings suggest that coronin 1A modulates endothelial cell apoptosis by regulating p38beta expression and activation. (PMID:25936522)
• p38beta was significantly higher in esophageal squamous cell carcinoma tissues compared with paired normal controls. p38beta expression was observed to be significantly associated with overall prognosis. (PMID:26666822)
• Results provide evidence that p38beta is an unusual enzyme that automodulates its basal, MAPKK-independent activity by several autophosphorylation events, which enhance and suppress its catalytic activity. (PMID:26976637)
• Suggest that R-Ras regulates angiogenic activities of endothelial cells in part via inhibition of the p38MAPK-HSP27 axis of VEGF signaling. (PMID:27029009)
• The two kinases HIPK3 and MAPK11 effect on Huntingtin (HTT)levels are mutant HTT protein (mHTT)-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. (PMID:29151587)
• Knocking down of LINC01220 inhibits proliferation and induces apoptosis of endometrial carcinoma through silencing MAPK11. (PMID:31123170)
• the present results suggested that p38a knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38b may not be involved in melanoma tumorigenesis. (PMID:31661126)
• Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11. (PMID:31822654)
• HuR stabilizes HTT mRNA via interacting with its exon 11 in a mutant HTT-dependent manner. (PMID:31928144)
• p38beta (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models. (PMID:33310004)
• Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway. (PMID:33524056)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk11	ENSDARG00000045836
danio_rerio		ENSDARG00000110143
mus_musculus	Mapk11	ENSMUSG00000053137
rattus_norvegicus	Mapk11	ENSRNOG00000006984
drosophila_melanogaster	p38a	FBGN0015765
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
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), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Mitogen-activated protein kinase 11 — Q15759 (reviewed: Q15759)

Alternative names: Mitogen-activated protein kinase p38 beta, Stress-activated protein kinase 2b, p38-2

All UniProt accessions (2): F8WDP4, Q15759

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on ‘Ser-10’ (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis. Phosphorylates methyltransferase DOT1L on ‘Ser-834’, ‘Thr-900’, ‘Ser-902’, ‘Thr-984’, ‘Ser-1001’, ‘Ser-1009’ and ‘Ser-1104’.

Subunit / interactions. Interacts with HDAC3 and DUSP16.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.

Activity regulation. Activated by phosphorylation on threonine and tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by environmental stress. HDAC3 interacts directly and selectively with MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Inhibited by SB203580 and pyridinyl-imidazole related compounds.

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 (2)

UniProt ID	Names	Canonical?
Q15759-1	1	yes
Q15759-3	2

RefSeq proteins (1): NP_002742* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003527	MAP_kinase_CS	Conserved_site
IPR008352	MAPK_HOG-like	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
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 (60 total): helix 20, strand 11, turn 6, modified residue 3, splice variant 3, sequence conflict 3, binding site 3, sequence variant 2, mutagenesis site 2, region of interest 2, chain 1, domain 1, short sequence motif 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3GP0	X-RAY DIFFRACTION	1.9
3GC9	X-RAY DIFFRACTION	2.05
3GC8	X-RAY DIFFRACTION	2.4
8YGW	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15759-F1	89.88	0.74

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): 150 (proton acceptor)

Ligand- & substrate-binding residues (3): 30–38; 53; 71

Post-translational modifications (3): 180, 182, 323

Mutagenesis-validated functional residues (2):

Position	Phenotype
180	inactivation.
182	inactivation.

Function

Pathways and Gene Ontology

Reactome pathways

61 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-171007	p38MAPK events
R-HSA-198753	ERK/MAPK targets
R-HSA-2151209	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450341	Activation of the AP-1 family of transcription factors
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-525793	Myogenesis
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
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-166520	Signaling by NTRKs
R-HSA-167044	Signalling to RAS
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

MSigDB gene sets: 351 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, KEGG_MAPK_SIGNALING_PATHWAY

GO Biological Process (22): osteoblast differentiation (GO:0001649), positive regulation of gene expression (GO:0010628), stress-activated protein kinase signaling cascade (GO:0031098), positive regulation of interleukin-12 production (GO:0032735), intracellular signal transduction (GO:0035556), p38MAPK cascade (GO:0038066), positive regulation of muscle cell differentiation (GO:0051149), stress-activated MAPK cascade (GO:0051403), cardiac muscle cell proliferation (GO:0060038), negative regulation of cardiac muscle cell proliferation (GO:0060044), bone development (GO:0060348), cellular response to interleukin-1 (GO:0071347), cellular response to UV-B (GO:0071493), cellular senescence (GO:0090398), cellular response to virus (GO:0098586), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), cellular response to stress (GO:0033554), protein maturation (GO:0051604), regulation of cardiac muscle cell proliferation (GO:0060043), pyroptotic inflammatory response (GO:0070269), NLRP1 inflammasome complex assembly (GO:1904784)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-19 pathways:

Category	Pathways
MAPK targets/ Nuclear events mediated by MAP kinases	2
Toll Like Receptor 4 (TLR4) Cascade	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Signalling to RAS	1
Nuclear Events (kinase and transcription factor activation)	1
Mitochondrial biogenesis	1
Cellular Senescence	1
Signaling by VEGF	1
MAP kinase activation	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1
Developmental Biology	1
RHO GTPase Effectors	1
Regulation of TP53 Activity	1
p53-Independent G1/S DNA Damage Checkpoint	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	3
cellular anatomical structure	3
gene expression	2
cellular response to stress	2
intracellular anatomical structure	2
cardiac muscle cell proliferation	2
protein kinase activity	2
ossification	1
cell differentiation	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
intracellular signal transduction	1
positive regulation of cytokine production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
signal transduction	1
muscle cell differentiation	1
positive regulation of cell differentiation	1
regulation of muscle cell differentiation	1
stress-activated protein kinase signaling cascade	1
striated muscle cell proliferation	1
cardiac muscle tissue growth	1
negative regulation of cell population proliferation	1
negative regulation of cardiac muscle tissue growth	1
regulation of cardiac muscle cell proliferation	1
skeletal system development	1
animal organ development	1
response to interleukin-1	1
cellular response to cytokine stimulus	1
response to UV-B	1
cellular response to UV	1
cellular process	1
response to virus	1
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
response to stress	1
cellular response to stimulus	1
protein metabolic process	1
regulation of cell population proliferation	1

Protein interactions and networks

STRING

4916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK11	JUN	P05412	709
MAPK11	MAPKAPK2	P49137	692
MAPK11	ATF2	P15336	682
MAPK11	DUSP1	P28562	674
MAPK11	CASP3	P42574	666
MAPK11	MAPK12	P53778	657
MAPK11	BCL2	P10415	640
MAPK11	PLXNB2	O15031	635
MAPK11	STAT1	P42224	631
MAPK11	HSPB1	P04792	605
MAPK11	HSPB2	Q16082	605
MAPK11	TNF	P01375	593
MAPK11	MEF2A	Q02078	590
MAPK11	HSPB3	Q12988	583
MAPK11	IL1B	P01584	581

IntAct

90 interactions, top by confidence:

A	B	Type	Score
MAPK11	MAPKAPK3	psi-mi:“MI:0915”(physical association)	0.870
MAPKAPK3	MAPK11	psi-mi:“MI:0914”(association)	0.870
MAPKAPK3	MAPK11	psi-mi:“MI:0915”(physical association)	0.870
MAPKAPK2	MAPK11	psi-mi:“MI:0914”(association)	0.730
CRYAA	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
MAPK11	DNM2	psi-mi:“MI:0915”(physical association)	0.560
MAPK11	ATN1	psi-mi:“MI:0915”(physical association)	0.560
MAPK11		psi-mi:“MI:0915”(physical association)	0.560
MAPK11	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
PAK1	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
PRKCA	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
KLK6	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
MAPK11	SMN1	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
MAPK11	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
KAT5	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
MAPK11	GIPC1	psi-mi:“MI:0915”(physical association)	0.560
LMO3	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	MAPK11	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (64): MAPK11 (Affinity Capture-MS), HDAC1 (Co-fractionation), PPM1G (Co-fractionation), TAB1 (Co-localization), MAPK11 (Affinity Capture-MS), MAPK11 (Affinity Capture-MS), MAPK11 (Affinity Capture-MS), MAPK11 (Affinity Capture-MS), MAPK11 (Affinity Capture-MS), MAPK11 (Affinity Capture-MS), MAPK11 (Far Western), MAPK11 (Reconstituted Complex), MAPK11 (Affinity Capture-Western), PML (Reconstituted Complex), MAPK11 (Biochemical Activity)

ESM2 similar proteins: A0A194WDG1, A0A1B5KW97, A1CAF0, A1DES4, A3EZ55, B0Y462, B0Y4X4, G4N374, O02812, O08911, O13352, O15264, O42376, O44408, O61443, O62618, P14681, P47811, P47812, P53778, P54666, P70618, Q0CIC7, Q0J4I1, Q15759, Q16539, Q17446, Q2U469, Q38HL5, Q3T0N5, Q4WQR3, Q4WUN7, Q54QB1, Q5J4W4, Q63538, Q8GYQ5, Q90336, Q92207, Q95NE7, Q966Y3

Diamond homologs: A0A1B5KW97, A0A1S3Z5Y0, A0A5B9GBF0, A1CAF0, A1CPG7, A1D2C9, A1DES4, A1IVT7, A2QN07, A2QRF6, A2XFC8, A3EZ53, A3EZ54, A3EZ55, A3LN91, A9S9Q8, A9T142, B0XR80, B0Y462, G1XJZ4, M1T7M3, O02812, O08911, O42376, O59853, O59854, O61443, O62618, O93982, P0C431, P0CP68, P0CP69, P32485, P42525, P47811, P47812, P53778, P70618, Q06060, Q07176

SIGNOR signaling

40 interactions.

A	Effect	B	Mechanism
TRIM27	up-regulates	MAPK11
MAPK11	up-regulates	KRT8	phosphorylation
MAPK11	up-regulates	HBP1	phosphorylation
“SB 203580”	down-regulates	MAPK11	“chemical inhibition”
MAPK11	up-regulates	TCF3	phosphorylation
MAPK11	down-regulates	EGFR	phosphorylation
SPAG9	up-regulates	MAPK11	binding
MAPK11	up-regulates	TP53	phosphorylation
MAPK11	up-regulates	RUNX2
MAPK11	down-regulates	SMAD2	phosphorylation
MAPK11	up-regulates	TWIST1	phosphorylation
MAPK11	unknown	RPTOR	phosphorylation
MAPK11	unknown	EWSR1	phosphorylation
(-)-anisomycin	up-regulates	MAPK11	“chemical activation”
SB-202190	down-regulates	MAPK11	“chemical inhibition”
VX-745	down-regulates	MAPK11	“chemical inhibition”
MAPK11	unknown	mTORC1	phosphorylation
MAPK11	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
MAPK11	“up-regulates quantity by expression”	HBA1	“transcriptional regulation”
regorafenib	“down-regulates activity”	MAPK11	“chemical inhibition”
MAPK11	“up-regulates activity”	PIAS2	phosphorylation
MAPK11	“down-regulates activity”	MEK1/2
MAPK11	“down-regulates activity”	MAPT	phosphorylation
MAPK11	“down-regulates quantity by destabilization”	CCND3	phosphorylation
MAPK11	“up-regulates activity”	MEF2A	phosphorylation
MAPK11	“up-regulates activity”	MEF2C	phosphorylation
MAP2K6	up-regulates	MAPK11	phosphorylation
MAPK11	up-regulates	MAPKAPK5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Signalling to ERKs	5	81.2×	2e-06
MAP kinase activation	5	41.7×	1e-05
Interleukin-17 signaling	5	34.3×	2e-05
Signaling by NTRK1 (TRKA)	6	31.9×	7e-06
Signaling by VEGF	5	29.7×	3e-05
Signaling by NTRKs	6	29.4×	8e-06
Toll Like Receptor 10 (TLR10) Cascade	5	29.1×	3e-05
Toll Like Receptor 5 (TLR5) Cascade	5	29.1×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	7	26.2×	6e-06
positive regulation of ERK1 and ERK2 cascade	6	12.5×	2e-03
protein stabilization	6	9.8×	3e-03
DNA damage response	7	9.1×	2e-03
intracellular signal transduction	8	7.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	31
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3062451	GRCh37/hg19 22q13.2-13.33(chr22:43107363-51156692)x1	Pathogenic

SpliceAI

1668 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50265028:C:CC	acceptor_gain	1.0000
22:50265316:CTCA:C	donor_loss	1.0000
22:50265317:TCA:T	donor_loss	1.0000
22:50265318:CAC:C	donor_loss	1.0000
22:50265319:A:AC	donor_gain	1.0000
22:50265319:AC:A	donor_gain	1.0000
22:50265319:ACC:A	donor_gain	1.0000
22:50265319:ACCC:A	donor_loss	1.0000
22:50265320:C:CA	donor_gain	1.0000
22:50265320:C:CC	donor_gain	1.0000
22:50265320:C:CG	donor_loss	1.0000
22:50265320:CCC:C	donor_gain	1.0000
22:50265320:CCCTT:C	donor_gain	1.0000
22:50266952:T:TA	donor_gain	1.0000
22:50267283:TGTA:T	acceptor_gain	1.0000
22:50267287:C:CC	acceptor_gain	1.0000
22:50267365:CCCCA:C	donor_loss	1.0000
22:50267366:CCCA:C	donor_loss	1.0000
22:50267367:CCA:C	donor_loss	1.0000
22:50267368:CACCT:C	donor_loss	1.0000
22:50267370:C:G	donor_loss	1.0000
22:50267480:TACC:T	acceptor_loss	1.0000
22:50267481:ACCTG:A	acceptor_loss	1.0000
22:50267482:CCTGG:C	acceptor_loss	1.0000
22:50267568:CA:C	donor_gain	1.0000
22:50267818:A:AC	donor_gain	1.0000
22:50267819:C:CA	donor_gain	1.0000
22:50267819:CGTT:C	donor_gain	1.0000
22:50267822:T:A	donor_gain	1.0000
22:50270174:TA:T	donor_loss	1.0000

AlphaMissense

2371 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:50266603:A:G	W207R	1.000
22:50266603:A:T	W207R	1.000
22:50267032:A:G	L171P	1.000
22:50267035:C:T	G170E	1.000
22:50267040:A:C	D168E	1.000
22:50267040:A:T	D168E	1.000
22:50267041:T:A	D168V	1.000
22:50267041:T:G	D168A	1.000
22:50267172:G:C	D150E	1.000
22:50267172:G:T	D150E	1.000
22:50267173:T:A	D150V	1.000
22:50267173:T:C	D150G	1.000
22:50267173:T:G	D150A	1.000
22:50267258:C:G	R149P	1.000
22:50267857:C:G	R70P	1.000
22:50267907:C:A	K53N	1.000
22:50267907:C:G	K53N	1.000
22:50270241:A:G	W18R	1.000
22:50270241:A:T	W18R	1.000
22:50265327:A:G	W337R	0.999
22:50265327:A:T	W337R	0.999
22:50265448:C:A	R296S	0.999
22:50265448:C:G	R296S	0.999
22:50266589:G:C	C211W	0.999
22:50266593:C:T	G210D	0.999
22:50266599:G:A	S208F	0.999
22:50266601:C:A	W207C	0.999
22:50266601:C:G	W207C	0.999
22:50266608:T:A	D205V	0.999
22:50266608:T:G	D205A	0.999

dbSNP variants (sampled 300 via entrez): RS1000047257 (22:50269722 C>T), RS1000207883 (22:50271851 G>A,C,T), RS1000261988 (22:50271600 G>A), RS1000266306 (22:50268620 G>A), RS1000452403 (22:50265622 C>G,T), RS1001030467 (22:50263326 C>G), RS1001158941 (22:50267783 G>A,C,T), RS1002457525 (22:50269402 A>C), RS1002682735 (22:50263827 A>C), RS1002717648 (22:50266776 GC>G), RS1002741965 (22:50269720 T>G), RS1003290929 (22:50265246 C>A,T), RS1003315587 (22:50270906 C>T), RS1003373720 (22:50264013 G>C), RS1003393164 (22:50271970 C>A,G,T)

Disease associations

OMIM: gene MIM:602898 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002481_12	Acne (severe)	4.000000e-06
GCST010988_517	Adult body size	1.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2094115 (PROTEIN FAMILY), CHEMBL3961 (SINGLE PROTEIN), CHEMBL4106180 (PROTEIN FAMILY), CHEMBL6177903 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

33 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 290,226 (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
CHEMBL267495	NALFURAFINE	4	310
CHEMBL5416410	DASATINIB	4	655
CHEMBL941	IMATINIB	4	111,611
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL1088752	LOSMAPIMOD	3	865
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL119385	NEFLAMAPIMOD	2	1,603
CHEMBL363648	TAK-715	2	442
CHEMBL1088751	PH-797804	2	700
CHEMBL1090089	PAMAPIMOD	2	428
CHEMBL1090090	VX-702	2	1,045
CHEMBL1230065	BMS-582949	2	121
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1738757	REBASTINIB	2
CHEMBL1938400	PF-03715455	2
CHEMBL2029988	CEP-32496	2
CHEMBL206834	BAFETINIB	2
CHEMBL3991932	PEXMETINIB	2
CHEMBL4129018	MW-150	2
CHEMBL514201	TALMAPIMOD	2
CHEMBL3577124	LY-3009120	1
CHEMBL1090173	SD-0006	1
CHEMBL1230122	R-1487	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — p38 subfamily

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
compound 4e [PMID: 35546685]	Inhibition	9.7	pIC50
ralimetinib	Inhibition	9.0	pIC50
doramapimod	Inhibition	8.15	pIC50
VX-702	Inhibition	7.77	pKd
pexmetinib	Inhibition	7.59	pIC50
PH-797804	Inhibition	7.4	pKi
talmapimod	Inhibition	7.01	pIC50
SB203580	Inhibition	7.0	pKi
pamapimod	Inhibition	6.92	pKd
TAK-715	Inhibition	6.7	pIC50
neflamapimod	Inhibition	6.66	pIC50

Binding affinities (BindingDB)

9 measured of 9 human assays (9 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
CHEMBL142697	IC50	0.4 nM
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
CHEMBL142187	IC50	20 nM
BMS-354825	KD	27 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM

ChEMBL bioactivities

1179 potent at pChembl≥5 of 1245 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.33	Ki	0.047	nM	CHEMBL194813
10.30	Ki	0.05	nM	CHEMBL363643
10.24	Ki	0.057	nM	CHEMBL196741
10.24	Ki	0.057	nM	CHEMBL197206
10.01	Kd	0.097	nM	DORAMAPIMOD
10.00	Kd	0.1	nM	CHEMBL318810
10.00	IC50	0.1	nM	CHEMBL303144
10.00	IC50	0.1	nM	CHEMBL5174953
9.96	IC50	0.11	nM	CHEMBL305178
9.82	Ki	0.15	nM	CHEMBL195532
9.82	IC50	0.15	nM	CHEMBL545353
9.80	Ki	0.16	nM	CHEMBL197351
9.72	IC50	0.19	nM	CHEMBL303144
9.70	IC50	0.2	nM	CHEMBL356125
9.70	IC50	0.2	nM	CHEMBL357598
9.70	IC50	0.2	nM	CHEMBL69319
9.70	IC50	0.2	nM	CHEMBL5206328
9.70	IC50	0.2	nM	CHEMBL5202475
9.60	IC50	0.25	nM	CHEMBL199679
9.40	IC50	0.4	nM	CHEMBL142697
9.40	IC50	0.4	nM	CHEMBL142187
9.40	IC50	0.4	nM	CHEMBL92082
9.40	IC50	0.4	nM	CHEMBL5184542
9.40	IC50	0.4	nM	CHEMBL446404
9.39	Ki	0.41	nM	CHEMBL274257
9.39	Ki	0.41	nM	CHEMBL198876
9.38	Ki	0.42	nM	CHEMBL274257
9.30	IC50	0.5	nM	CHEMBL327987
9.30	IC50	0.5	nM	CHEMBL119595
9.29	IC50	0.51	nM	CHEMBL219796
9.22	IC50	0.6	nM	CHEMBL328242
9.22	IC50	0.6	nM	CHEMBL331252
9.22	IC50	0.6	nM	CHEMBL161276
9.21	Ki	0.61	nM	CHEMBL382954
9.19	IC50	0.65	nM	CHEMBL3220549
9.17	Kd	0.67	nM	CHEMBL1089865
9.16	IC50	0.69	nM	CHEMBL219804
9.15	IC50	0.7	nM	CHEMBL92814
9.14	IC50	0.72	nM	CHEMBL2402001
9.13	IC50	0.74	nM	CHEMBL388582
9.12	IC50	0.75	nM	CHEMBL308939
9.10	IC50	0.8	nM	CHEMBL343682
9.10	IC50	0.8	nM	CHEMBL142289
9.10	IC50	0.8	nM	CHEMBL92082
9.10	IC50	0.8	nM	NEFLAMAPIMOD
9.10	Ki	0.8	nM	NEFLAMAPIMOD
9.10	IC50	0.8	nM	CHEMBL5197888
9.09	IC50	0.82	nM	CHEMBL1738839
9.04	IC50	0.91	nM	CHEMBL325211
9.01	Ki	0.97	nM	CHEMBL383137

PubChem BioAssay actives

1154 with measured affinity, of 3561 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
3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]-2-(methylamino)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	<0.0001	uM
3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]-2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0001	uM
3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0001	uM
3-[[2-amino-5-cyano-6-[2,2-dimethylpropyl(methyl)amino]pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0001	uM
3-[[2-amino-5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0001	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	127075: Binding affinity against human Mitogen-activated protein kinase p38 kinase evaluated by exchange curve	kd	0.0001	uM
4-[3-methyl-2-piperidin-4-yl-5-[3-(trifluoromethyl)phenyl]imidazol-4-yl]-N-[(1S)-1-phenylethyl]pyrimidin-2-amine	127106: Inhibition of Mitogen-activated protein kinase p38	ic50	0.0001	uM
N-[(1S)-1-phenylethyl]-4-[6-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]pyridazin-4-yl]pyrimidin-2-amine;dihydrochloride	127106: Inhibition of Mitogen-activated protein kinase p38	ic50	0.0001	uM
1-[3-tert-butyl-1-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[(2S,6R)-2,6-dimethylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910480: Inhibition of recombinant human full length His-tagged p38beta expressed in baculovirus expression system preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0001	uM
4-[3-methyl-2-piperidin-4-yl-5-[3-(trifluoromethyl)phenyl]imidazol-4-yl]-N-[(1S)-1-phenylethyl]pyridin-2-amine	381535: Inhibition of wild type p38beta	ic50	0.0001	uM
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	1525522: Binding affinity to P38 mitogen activated protein kinase (unknown origin)	kd	0.0001	uM
3-[[2-amino-5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0002	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(piperidin-4-ylamino)-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0002	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)quinolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0002	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[(1S,4R)-4-[(3-propan-2-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910480: Inhibition of recombinant human full length His-tagged p38beta expressed in baculovirus expression system preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0002	uM
1-[3-tert-butyl-1-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[(2S)-2-methylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910480: Inhibition of recombinant human full length His-tagged p38beta expressed in baculovirus expression system preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0002	uM
2-[5-[2-(cyclopropylmethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1H-imidazol-2-yl]-N,N,5-trimethyl-1,3-dioxane-5-carboxamide	209043: Inhibition of p38-related TNF alpha release by human monocyte cell line (THP-1)	ic50	0.0002	uM
7-(1-tert-butylpiperidin-4-yl)-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)quinolin-2-one	381535: Inhibition of wild type p38beta	ic50	0.0003	uM
6-(4-fluorophenyl)-7-[2-[[(1S)-1-phenylethyl]amino]pyrimidin-4-yl]-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-5-one	215246: Inhibition of LPS-stimulated p38-related TNF-alpha production in human peripheral blood mononuclear cells (PBMC)	ic50	0.0004	uM
N-[(1R)-1-phenylethyl]-4-[2-piperidin-4-yl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]pyrimidin-2-amine	92862: Inhibition of LPS-induced release of Tumor necrosis factor-alpha (TNF-alpha) from human whole blood	ic50	0.0004	uM
3-[[5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0004	uM
3-[[5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0004	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino]-3,4-dihydroquinazolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0004	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino]-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0004	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[(1S,4R)-4-[(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910480: Inhibition of recombinant human full length His-tagged p38beta expressed in baculovirus expression system preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0004	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(piperidin-4-ylamino)-3,4-dihydroquinazolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0005	uM
3-[2-[[(2S)-1-methoxypropan-2-yl]amino]-4-pyridinyl]-2-phenylimidazo[1,2-a]pyrimidin-7-amine	155458: Inhibition of LPS-induced p38-related TNF-alpha production in human peripheral blood mononuclear cells	ic50	0.0005	uM
5-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(methylamino)-1,6-naphthyridin-2-one	274335: Inhibition of p38	ic50	0.0005	uM
N-[(1S)-1-phenylethyl]-4-[6-piperazin-1-yl-3-[3-(trifluoromethyl)phenyl]pyridazin-4-yl]pyrimidin-2-amine	127106: Inhibition of Mitogen-activated protein kinase p38	ic50	0.0006	uM
3-[[5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0006	uM
5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)-3,4-dihydroquinazolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0006	uM
2-phenyl-3-[2-[[(1S)-1-phenylethyl]amino]pyrimidin-4-yl]imidazo[1,2-a]pyrimidin-7-amine	155458: Inhibition of LPS-induced p38-related TNF-alpha production in human peripheral blood mononuclear cells	ic50	0.0006	uM
1-(2,6-dichlorophenyl)-6-(2,4-difluorophenyl)sulfanyl-7-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-3,4-dihydropyrido[3,2-d]pyrimidin-2-one	209193: Anti human TNF-alpha activity determined through TNF-alpha release was measured in the supernatants by ELISA	ic50	0.0007	uM
N-cyclopropyl-3-[1-(2,6-difluorophenyl)-7-methyl-6-oxopyrazolo[5,4-b]pyridin-5-yl]-4-methylbenzamide	476167: Binding affinity to p38beta	kd	0.0007	uM
7-amino-5-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-1,6-naphthyridin-2-one	274335: Inhibition of p38	ic50	0.0007	uM
3,4-dihydro-1H-quinolin-2-one	286353: Inhibition of mitogen-activated protein kinase p38 at 2 uM ATP	ic50	0.0007	uM
N-[5-(cyclopropylcarbamoyl)-2-methylphenyl]-5-(6-methyl-3-pyridinyl)thiophene-2-carboxamide	758209: Inhibition of p38 MAPK-mediated TNFalpha production in LPS-induced human whole blood preincubated for 5 mins prior to LPS-treatment measured after 6 hrs by ELISA	ic50	0.0007	uM
N-[(1S)-1-phenylethyl]-4-[2-piperidin-4-yl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]pyrimidin-2-amine	127243: Inhibition of Mitogen-activated protein kinase p38	ic50	0.0008	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0008	uM
8-(2,6-dichlorophenyl)-4-(2,4-difluorophenyl)-7-oxido-2-piperidin-4-yl-1,7-naphthyridin-7-ium	1504524: Inhibition of MAPK p38 (unknown origin)	ic50	0.0008	uM
5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one	1525523: Inhibition of P38 mitogen activated protein kinase (unknown origin)	ki	0.0008	uM
5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)-3,4-dihydroquinolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0008	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910480: Inhibition of recombinant human full length His-tagged p38beta expressed in baculovirus expression system preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0008	uM
2-(4-fluorophenyl)-4-phenylmethoxy-3-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-6-amine	222608: Inhibition of TNF-alpha production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells	ic50	0.0009	uM
3-[[5-cyano-6-(propylamino)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0010	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-naphthalen-1-ylurea	127076: Binding affinity for human recombinant Mitogen-activated protein kinase p38 in a fluorescent binding assay	kd	0.0010	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0011	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0011	uM
N-[4-[2-(4-fluoro-3-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridinyl]-6-methylpyridine-3-carboxamide	1388757: Inhibition of MAPK p38 in human THP1 cells assessed as reduction in LPS-induced TNFalpha production preincubated for 60 mins followed by LPS addition measured after 4 hrs by HTRF assay	ic50	0.0012	uM
7-[5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(2,6-dichlorophenyl)-6-(2,4-difluorophenyl)sulfanyl-3,4-dihydropyrido[3,2-d]pyrimidin-2-one	209193: Anti human TNF-alpha activity determined through TNF-alpha release was measured in the supernatants by ELISA	ic50	0.0012	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression, increases methylation	5
sodium arsenite	increases activity, increases phosphorylation, increases expression	3
SB 203580	decreases reaction, increases expression, increases phosphorylation, decreases activity, decreases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance	3
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases activity	2
Arsenic Trioxide	affects binding, decreases reaction, increases activity	2
Cadmium	increases expression, increases abundance, increases phosphorylation	2
Cisplatin	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases reaction	2
Ozone	affects cotreatment, decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases expression, increases abundance, increases phosphorylation	2
GSK-J4	decreases expression	1
taiwanin E	decreases expression, increases reaction	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
afimoxifene	decreases response to substance	1
butyraldehyde	increases expression	1
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
pentanal	increases expression	1
xanthohumol	decreases phosphorylation	1
obeticholic acid	decreases expression	1
nutlin 3	increases expression, affects cotreatment	1
abrine	decreases expression	1
asparanin A	increases expression	1
(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)	increases phosphorylation	1
jinfukang	affects cotreatment, increases expression	1
2,3-dihydroquinolin-4(1H)-one	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1

ChEMBL screening assays

951 unique, capped per target: 893 binding, 56 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004015	Binding	Inhibition of human p38 MAPK	Hepatitis C virus NS5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. — J Biol Chem
CHEMBL4181658	ADMET	Inhibition of P38 (unknown origin)	Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors. — Bioorg Med Chem Lett
CHEMBL697600	Functional	Inhibition of LPS-induced p38-related TNF alpha release from human monocytes	Pyrroles and other heterocycles as inhibitors of p38 kinase. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7UI	Ubigene A-549 MAPK11 KO	Cancer cell line	Male
CVCL_D9JL	Ubigene HEK293 MAPK11 KO	Transformed cell line	Female
CVCL_SW85	HAP1 MAPK11 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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