MAPK12

Summary

MAPK12 (mitogen-activated protein kinase 12, HGNC:6874) is a protein-coding gene on chromosome 22q13.33, encoding Mitogen-activated protein kinase 12 (P53778). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

Activation of members of the mitogen-activated protein kinase family is a major mechanism for transduction of extracellular signals. Stress-activated protein kinases are one subclass of MAP kinases. The protein encoded by this gene functions as a signal transducer during differentiation of myoblasts to myotubes.

Source: NCBI Gene 6300 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 72 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6874
Approved symbol	MAPK12
Name	mitogen-activated protein kinase 12
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	ERK6, PRKM12, p38gamma, SAPK-3
Ensembl gene	ENSG00000188130
Ensembl biotype	protein_coding
OMIM	602399
Entrez	6300

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000215659, ENST00000395778, ENST00000395780, ENST00000467891, ENST00000482969, ENST00000488504, ENST00000492218, ENST00000496942, ENST00000497036, ENST00000497738, ENST00000622558, ENST00000901189, ENST00000927611, ENST00000927612, ENST00000947313, ENST00000947314, ENST00000947315, ENST00000947316

RefSeq mRNA: 2 — MANE Select: NM_002969 NM_001303252, NM_002969

CCDS: CCDS14089, CCDS77688

Canonical transcript exons

ENST00000215659 — 12 exons

Exon	Start	End
ENSE00001825407	50261385	50261683
ENSE00003480988	50255615	50255694
ENSE00003481718	50255810	50255881
ENSE00003494103	50255197	50255370
ENSE00003552950	50257082	50257193
ENSE00003579733	50258243	50258301
ENSE00003594524	50261167	50261296
ENSE00003621291	50256085	50256199
ENSE00003624982	50256935	50256964
ENSE00003638962	50255453	50255531
ENSE00003675376	50256599	50256646
ENSE00003851007	50252901	50253480

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3441 / max 119.1715, expressed in 1494 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194716	3.7336	1274
194714	3.0766	1212
194717	1.3534	826
194715	0.1804	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.72	gold quality
muscle of leg	UBERON:0001383	97.14	gold quality
muscle organ	UBERON:0001630	96.68	gold quality
triceps brachii	UBERON:0001509	96.66	gold quality
vastus lateralis	UBERON:0001379	96.24	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.19	gold quality
diaphragm	UBERON:0001103	95.87	gold quality
quadriceps femoris	UBERON:0001377	95.81	gold quality
skeletal muscle tissue	UBERON:0001134	95.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.81	gold quality
adenohypophysis	UBERON:0002196	94.31	gold quality
gluteal muscle	UBERON:0002000	94.22	gold quality
cerebellar hemisphere	UBERON:0002245	93.86	gold quality
cerebellar cortex	UBERON:0002129	93.66	gold quality
biceps brachii	UBERON:0001507	93.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.18	gold quality
apex of heart	UBERON:0002098	92.82	gold quality
pituitary gland	UBERON:0000007	92.58	gold quality
right frontal lobe	UBERON:0002810	92.34	gold quality
body of uterus	UBERON:0009853	92.20	gold quality
stromal cell of endometrium	CL:0002255	92.05	gold quality
muscle tissue	UBERON:0002385	91.94	gold quality
left uterine tube	UBERON:0001303	91.66	gold quality
cerebellum	UBERON:0002037	91.38	gold quality
right ovary	UBERON:0002118	91.12	gold quality
deltoid	UBERON:0001476	90.83	gold quality
cingulate cortex	UBERON:0003027	89.60	gold quality
anterior cingulate cortex	UBERON:0009835	89.51	gold quality
left ovary	UBERON:0002119	89.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.37

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
JUNB	Activation

Upstream regulators (CollecTRI, top): ESR1, JUN, MYOD1, MYOG, TP53

miRNA regulators (miRDB)

16 targeting MAPK12, 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-3667-3P	99.99	67.17	1636
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-198	98.70	67.32	920
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675
HSA-MIR-4268	94.45	64.09	819
HSA-MIR-9899	91.24	59.59	90

Literature-anchored findings (GeneRIF, showing 40)

• C-terminal halves of ERK2 and ERK3DeltaC are primarily responsible for subcellular localization in resting cells; and the N-terminal folding domain of ERK2 is required for its activation in cells, interaction with MEK1, and accumulation in the nucleus (PMID:11741894)
• Cardiac expression and subcellular localization (PMID:11991731)
• IL-2 and polysaccharide K increased the expression of ERK3. (PMID:12536241)
• CRM1 binds to ERK3and promotes the cytoplasmic relocalization of ERK3. Enforced localization of ERK3 in the nucleus or cytoplasm markedly attenuates the ability of the kinase to induce cell cycle arrest in fibroblasts. (PMID:12915405)
• data suggest that p38gamma increases basal glucose uptake and decreases DNP- and contraction-stimulated glucose uptake, partially by affecting levels of glucose transporter expression in skeletal muscle (PMID:14592936)
• SAPK3 phosphorylates mitochondrial protein Sab (PMID:15158451)
• Data show that in response to radiation, MRK controls two independent pathways: the Chk2-Cdc25A pathway leading to cell cycle arrest and the p38gamma MAPK pathway. (PMID:15342622)
• hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription (PMID:17088247)
• Mapk14 antagonizes Mapk12 activity through c-jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. (PMID:17724032)
• These results suggest that, in SupT1-based cell lines, p38alpha, p38gamma and p38delta, but not p38beta, are implicated in both HIV-1 induced replication and apoptosis in infected and uninfected bystander cells. (PMID:18559936)
• p38alpha and p38gamma are essential components of the signaling pathway that regulates the tumor-suppressing senescence response (PMID:19251701)
• PTPH1 plays a role in Ras-dependent malignant growth of colon cancer by a mechanism depending on its p38gamma-binding activity. (PMID:20332238)
• In response to hyperosmotic stress, p38 also regulates formation of complexes between hDlg and PSF. (PMID:20605917)
• Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D. (PMID:20804750)
• The majority of p38gamma-depleted cells die at mitotic arrest or soon after abnormal exit from M-phase. (PMID:21172807)
• demonstrates that p38gamma MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor (PMID:21532888)
• p38gamma mitogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. (PMID:21862636)
• a new paradigm in which p38gamma actively regulates the drug-Topo IIalpha signal transduction, and this may be exploited to increase the therapeutic activity of Topo II drugs. (PMID:21878638)
• phosphorylation at Ser-118 is required for ER to bind both p38gamma and c-Jun, thereby promoting ER relocation from ERE to AP-1 promoter sites. (PMID:22399296)
• Thus, in endothelial cells p38alpha mediates apoptotic signaling, whereas p38beta and p38gamma transduce survival signaling (PMID:22522454)
• p38gamma Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. (PMID:22730326)
• SEPW1 silencing increases MKK4, which activates p38gamma, p38delta, and JNK2 to phosphorylate p53 on Ser-33 and cause a transient G(1) arrest. (PMID:22730327)
• analysis of how allosteric regulation of p38gamma and PTPN3 involves a PDZ domain-modulated complex formation (PMID:25314968)
• This study reveals a novel pathway that directly links ErbB4 and p38gamma to the transcriptional machinery of NKx2.5-GATA4 complex which is critical for cardiomyocyte formation during mammalian heart development. (PMID:26418945)
• Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior. (PMID:26588708)
• There was significant association between p38gamma expression and esophageal squamous cell carcinoma clinical stage, lymph nodes metastases, and tumor volume. p38delta overexpression can promote tumorigenesis in nude mice model xenografted with Eca109 cells whose basal level of p38delta was stably over-expressed and p38gamma was stably knocked down. (PMID:26666822)
• during interphase ERK3 is mainly resident in the nucleoplasm in association with ribonuclear proteins involved in early pre-mRNA splicing, it undergoes cell cycle-dependent redistribution and, during apoptosis (PMID:26708186)
• p38gamma and p38delta reprogram liver metabolism by modulating neutrophil infiltration and provide a potential target for NAFLD therapy (PMID:26843485)
• the p38gamma.PTPN4 interaction promotes cellular signaling, preventing cell death induction. (PMID:27246854)
• NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38gamma. (PMID:27353957)
• study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression. (PMID:28079973)
• Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2 has been reported. (PMID:28252035)
• Our findings suggest that L290P/V mutations of ERK3 may confer increased invasiveness to cancers. (PMID:29101390)
• importance of Ser(189) phosphorylation for intramolecular regulation of ERK3 kinase activity and invasiveness-promoting ability in lung cancer cells. (PMID:30166347)
• Study established an important role of p38gamma MAPK in epithelial-mesenchymal transition (EMT) and identified a novel signaling pathway for p38gamma MAPK-mediated tumor promotion. p38gamma MAPK regulated miR-200b through inhibiting GATA3 by inducing its ubiquitination, leading proteasome-dependent degradation. (PMID:30251680)
• p38gamma was up-regulated in breast cancer, which exerts a great influence on the cell growth, cell mobility, invasiveness, and apoptosis of MDA-MB-231 cells and also affected the metabolism (PMID:30447427)
• IFN-gamma receptor stimulation requires ULK1-mediated activation of MLK3 and ERK5 (PMID:30459284)
• these results indicate that ERK3 acts as a potent suppressor of melanoma cell growth and invasiveness (PMID:30569573)
• p38 MAPK gamma (p38gamma) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle; p38gamma shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members; biopsies of human hepatocellular carcinoma show high expression of p38gamma, suggesting that p38gamma could be a therapeutic target in the treatment of this disease (PMID:30971822)
• P38GAMMA silencing inhibits colorectal cancer (CRC) cell growth and migration. P38GAMMA silencing induces apoptosis activation in CRC cells. Ectopic P38GAMMA overexpression promotes CRC cell progression in vitro. (PMID:31349971)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk12b	ENSDARG00000006409
danio_rerio	mapk12a	ENSDARG00000042021
mus_musculus	Mapk12	ENSMUSG00000022610
rattus_norvegicus	Mapk12	ENSRNOG00000031233
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), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386)

Protein

Protein identifiers

Mitogen-activated protein kinase 12 — P53778 (reviewed: P53778)

Alternative names: Extracellular signal-regulated kinase 6, Mitogen-activated protein kinase p38 gamma, Stress-activated protein kinase 3

All UniProt accessions (3): A8MY48, B5MDL5, P53778

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 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 such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.

Subunit / interactions. Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with SH3BP5. Interacts with LIN7C, SCRIB and SYNJ2BP. Interacts with PTPN4; this interaction induces the activation of PTPN4 phosphatase activity.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Highly expressed in skeletal muscle and heart.

Post-translational modifications. Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme. Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.

Disease relevance. MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples.

Activity regulation. Activated by phosphorylation on threonine and tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK12 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK12 activator in response to TNF.

Cofactor. Binds 2 magnesium ions.

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

Induction. Expression of MAPK12 is down-regulation by MAPK14 activation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P53778-1	1	yes
P53778-2	2

RefSeq proteins (2): NP_001290181, NP_002960* (*=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
IPR038786	MAPK12	Family
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 (56 total): helix 16, sequence conflict 10, strand 10, turn 5, sequence variant 3, mutagenesis site 3, binding site 2, modified residue 2, chain 1, domain 1, short sequence motif 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1CM8	X-RAY DIFFRACTION	2.4
4QUM	X-RAY DIFFRACTION	2.52
6UNA	X-RAY DIFFRACTION	2.55
7CGA	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53778-F1	88.33	0.70

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): 153 (proton acceptor)

Ligand- & substrate-binding residues (2): 33–41; 56

Post-translational modifications (2): 183, 185

Mutagenesis-validated functional residues (3):

Position	Phenotype
179	emulation of the active state.
185	loss of activity.
330	no effect.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-171007	p38MAPK events
R-HSA-2151209	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-525793	Myogenesis
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-1266738	Developmental Biology
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-167044	Signalling to RAS
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-187687	Signalling to ERKs
R-HSA-194138	Signaling by VEGF
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 211 (showing top): AP1_01, REACTOME_INNATE_IMMUNE_SYSTEM, TSENG_IRS1_TARGETS_UP, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, KEGG_MAPK_SIGNALING_PATHWAY, GOLDRATH_IMMUNE_MEMORY, MODULE_128, KEGG_FC_EPSILON_RI_SIGNALING_PATHWAY, PID_RHOA_PATHWAY, NIKOLSKY_BREAST_CANCER_22Q13_AMPLICON, REACTOME_SIGNALLING_TO_RAS, RICKMAN_METASTASIS_DN, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT

GO Biological Process (11): MAPK cascade (GO:0000165), signal transduction (GO:0007165), muscle organ development (GO:0007517), intracellular signal transduction (GO:0035556), signal transduction in response to DNA damage (GO:0042770), myoblast differentiation (GO:0045445), negative regulation of cell cycle (GO:0045786), positive regulation of muscle cell differentiation (GO:0051149), regulation of cell cycle (GO:0051726), protein phosphorylation (GO:0006468), cellular response to stress (GO:0033554)

GO Molecular Function (12): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), peptidase activator activity (GO:0016504), 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), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Signalling to RAS	1
Mitochondrial biogenesis	1
Signaling by VEGF	1
Developmental Biology	1
RAF/MAP kinase cascade	1
Organelle biogenesis and maintenance	1
Signalling to ERKs	1
Immune System	1
Innate Immune System	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of cellular process	2
cellular response to stimulus	2
muscle structure development	2
intracellular anatomical structure	2
cell cycle	2
protein kinase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
intracellular signaling cassette	1
cell communication	1
cellular process	1
signaling	1
animal organ development	1
signal transduction	1
DNA damage response	1
intracellular signal transduction	1
cell differentiation	1
negative regulation of cellular process	1
regulation of cell cycle	1
muscle cell differentiation	1
positive regulation of cell differentiation	1
regulation of muscle cell differentiation	1
phosphorylation	1
protein modification process	1
response to stress	1
metal ion binding	1
MAPK cascade	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
enzyme activator activity	1
peptidase activity	1
peptidase regulator activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1

Protein interactions and networks

STRING

4140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK12	SUV39H1	O43463	767
MAPK12	SNTA1	Q13424	749
MAPK12	JUN	P05412	708
MAPK12	PLXNB2	O15031	675
MAPK12	MAPK11	Q15759	657
MAPK12	RCSD1	Q6JBY9	656
MAPK12	IL6	P05231	621
MAPK12	HSPB1	P04792	591
MAPK12	MTOR	P42345	586
MAPK12	HSPB2	Q16082	584
MAPK12	TNF	P01375	582
MAPK12	CALM1	P02593	581
MAPK12	CALML3	P27482	581
MAPK12	DLG1	Q12959	581
MAPK12	CALML5	Q9NZT1	581

IntAct

182 interactions, top by confidence:

A	B	Type	Score
SCRIB	MAPK12	psi-mi:“MI:0915”(physical association)	0.790
SCRIB	MAPK12	psi-mi:“MI:0403”(colocalization)	0.790
SCRIB	MAPK12	psi-mi:“MI:0407”(direct interaction)	0.790
MAPK12	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.790
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
DLG1	MAPK12	psi-mi:“MI:0407”(direct interaction)	0.710
MAPK12	DLG1	psi-mi:“MI:2364”(proximity)	0.710
MAPK12	DLG1	psi-mi:“MI:0407”(direct interaction)	0.710
MAPK12	MAPK13	psi-mi:“MI:0914”(association)	0.640
PRP4K	PRPF4	psi-mi:“MI:0914”(association)	0.640
PTPN3	MAPK12	psi-mi:“MI:0203”(dephosphorylation reaction)	0.620
SNTB1	MAPK12	psi-mi:“MI:0407”(direct interaction)	0.620
MAPK12	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.620
MAPK12	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.620
MAP2K6	MAP2K3	psi-mi:“MI:0914”(association)	0.610
MAPK12	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.590
SIAH1	MAPK12	psi-mi:“MI:0915”(physical association)	0.560
MAPK12	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
APP	MAPK12	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (98): SIAH1 (Two-hybrid), MAPK12 (Affinity Capture-MS), MAPK13 (Affinity Capture-MS), MYLK3 (Affinity Capture-MS), MAPK12 (Co-fractionation), DLG1 (Co-localization), DUSP1 (Co-localization), RCSD1 (Biochemical Activity), MAPK12 (Affinity Capture-Western), MAPK13 (Affinity Capture-MS), MYLK3 (Affinity Capture-MS), MAPK12 (Affinity Capture-MS), MAPK12 (Affinity Capture-RNA), MAPK12 (Affinity Capture-Western), MAPK12 (Reconstituted Complex)

ESM2 similar proteins: A0A194WDG1, A1CAF0, A1DES4, A2QN07, B0Y462, B0Y4X4, G4N374, O02812, O08911, O13352, O15264, O42376, O44408, O59854, O61443, O62618, P14681, P39745, P47811, P50750, P53778, P70618, Q00772, Q06060, Q0CIC7, Q16539, Q17446, Q1L5Z8, Q39026, Q3T0N5, Q40532, Q4WQR3, Q4WUN7, Q5J4W4, Q63538, Q750A9, Q84UI5, Q8MXI4, Q92398, Q95NE7

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

32 interactions.

A	Effect	B	Mechanism
TRIM27	up-regulates	MAPK12
MAPK12	up-regulates	KRT8	phosphorylation
PPM1D	down-regulates	MAPK12	dephosphorylation
MAP2K6	up-regulates	MAPK12	phosphorylation
MAPK12	“down-regulates quantity by destabilization”	NUP62	phosphorylation
MAPK12	“up-regulates quantity”	PFKFB3	phosphorylation
MAPK12	“up-regulates activity”	TP53	phosphorylation
MAPK12	up-regulates	ATF2	phosphorylation
MAPK12	up-regulates	SNTA1	phosphorylation
MAPK12	“up-regulates quantity by expression”	JUNB	“transcriptional regulation”
TNFRSF17	up-regulates	MAPK12
MAP2K3	up-regulates	MAPK12	phosphorylation
MAPK12	“down-regulates activity”	CARM1	phosphorylation
SNTB1	down-regulates	MAPK12	binding
MAPK12	“up-regulates quantity by expression”	Satellite_cells_self-renewal	“transcriptional regulation”
SNTB1	down-regulates	MAPK12
MAPK12	“up-regulates activity”	MYOD1	phosphorylation
MAPK12	“down-regulates activity”	MAPT	phosphorylation
MAPK12	unknown	EEF2K	phosphorylation
MAPK12	unknown	SH3BP5	phosphorylation
MAPK12	“form complex”	MAPK12/CARM1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
Ras activation upon Ca2+ influx through NMDA receptor	5	34.8×	4e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	33.2×	4e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	33.2×	4e-05
Long-term potentiation	5	29.0×	7e-05
Assembly and cell surface presentation of NMDA receptors	9	27.9×	2e-08
Neurexins and neuroligins	9	21.6×	9e-08
Protein-protein interactions at synapses	5	16.2×	1e-03
RHOB GTPase cycle	5	9.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	56.1×	3e-14
receptor clustering	7	38.3×	2e-07
protein localization to synapse	5	33.6×	4e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	7	30.4×	9e-07
epidermal growth factor receptor signaling pathway	6	13.0×	6e-04
cell-cell adhesion	11	9.8×	3e-06
negative regulation of ERK1 and ERK2 cascade	5	9.5×	9e-03
protein-containing complex assembly	9	9.0×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

5132 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50245671:TCACC:T	donor_loss	1.0000
22:50245672:CACCT:C	donor_loss	1.0000
22:50245825:GTT:G	acceptor_gain	1.0000
22:50245825:GTTC:G	acceptor_loss	1.0000
22:50245826:TT:T	acceptor_gain	1.0000
22:50245827:TC:T	acceptor_loss	1.0000
22:50245828:C:CC	acceptor_gain	1.0000
22:50245834:C:CT	acceptor_gain	1.0000
22:50245834:C:T	acceptor_gain	1.0000
22:50245835:A:T	acceptor_gain	1.0000
22:50245904:GCTTA:G	donor_loss	1.0000
22:50245905:CTTA:C	donor_loss	1.0000
22:50245906:TTACC:T	donor_loss	1.0000
22:50245907:TACC:T	donor_loss	1.0000
22:50245908:A:C	donor_loss	1.0000
22:50245909:C:G	donor_loss	1.0000
22:50246869:GCTTA:G	donor_loss	1.0000
22:50246870:CTTAC:C	donor_loss	1.0000
22:50246871:TTA:T	donor_loss	1.0000
22:50246872:TA:T	donor_loss	1.0000
22:50246874:C:CT	donor_loss	1.0000
22:50246874:CCT:C	donor_gain	1.0000
22:50246962:TTCAC:T	acceptor_gain	1.0000
22:50246963:TCAC:T	acceptor_gain	1.0000
22:50246964:CAC:C	acceptor_gain	1.0000
22:50246964:CACC:C	acceptor_gain	1.0000
22:50246965:AC:A	acceptor_gain	1.0000
22:50246966:CC:C	acceptor_gain	1.0000
22:50246967:C:CC	acceptor_gain	1.0000
22:50246968:T:A	acceptor_loss	1.0000

AlphaMissense

2409 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:50255873:A:G	W210R	1.000
22:50255873:A:T	W210R	1.000
22:50256191:G:C	D171E	1.000
22:50256191:G:T	D171E	1.000
22:50256192:T:A	D171V	1.000
22:50256645:T:G	D153A	1.000
22:50256936:C:A	R152I	1.000
22:50261254:C:A	K56N	1.000
22:50261254:C:G	K56N	1.000
22:50261256:T:C	K56E	1.000
22:50255859:G:C	C214W	0.999
22:50255863:C:T	G213D	0.999
22:50255871:C:A	W210C	0.999
22:50255871:C:G	W210C	0.999
22:50255878:T:A	D208V	0.999
22:50255878:T:G	D208A	0.999
22:50255879:C:G	D208H	0.999
22:50256123:G:T	P194H	0.999
22:50256129:C:G	R192P	0.999
22:50256133:A:G	Y191H	0.999
22:50256141:G:A	T188I	0.999
22:50256183:A:G	L174P	0.999
22:50256192:T:C	D171G	0.999
22:50256192:T:G	D171A	0.999
22:50256193:C:G	D171H	0.999
22:50256198:A:G	I169T	0.999
22:50256627:A:G	L159P	0.999
22:50256629:G:C	N158K	0.999
22:50256629:G:T	N158K	0.999
22:50256631:T:C	N158D	0.999

dbSNP variants (sampled 300 via entrez): RS1000296740 (22:50260130 G>A), RS1000851417 (22:50257011 G>A), RS1001030467 (22:50263326 C>G), RS1001294966 (22:50262995 A>G), RS1001321934 (22:50259198 C>T), RS1001360190 (22:50261913 G>A,C), RS1001367191 (22:50253905 A>G), RS1001740242 (22:50255900 T>G), RS1001816641 (22:50253745 G>A,T), RS1002048799 (22:50254078 C>T), RS1002088336 (22:50259024 C>G), RS1002127966 (22:50254872 G>C), RS1002212449 (22:50255726 C>T), RS1002409554 (22:50262552 C>G,T), RS1002586203 (22:50261824 C>A,G)

Disease associations

OMIM: gene MIM:602399 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002481_12	Acne (severe)	4.000000e-06
GCST006479_72	Diverticular disease	8.000000e-07
GCST007680_6	Triiodothyronine levels and thyroxine levels	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0008392	triiodothyronine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2094115 (PROTEIN FAMILY), CHEMBL3038503 (PROTEIN FAMILY), CHEMBL4674 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 217,295 (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
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL119385	NEFLAMAPIMOD	2	1,603
CHEMBL363648	TAK-715	2	442
CHEMBL1088751	PH-797804	2	700
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL3681949	TOP-1288	2	192
CHEMBL3695568	JNJ-49095397	2	127
CHEMBL475251	R-406	2	762
CHEMBL3577124	LY-3009120	1	198
CHEMBL1084546	PF-00562271	1	399
CHEMBL482967	CYC-116	1	651
CHEMBL574738	AST-487	1	451

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
doramapimod	Inhibition	7.52	pIC50
compound 4e [PMID: 35546685]	Inhibition	6.03	pIC50

Binding affinities (BindingDB)

111 measured of 125 human assays (125 total across all organisms); most potent 50 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
Staurosporine	KD	1.7 nM
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-isopropylphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	9 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
N-[4-[4-[[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]-2-methoxyacetamide	IC50	12 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-(1-methylcyclopropyl)-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	19 nM	US-8933228: Respiratory formulations and compounds for use therein
CHEMBL142187	IC50	20 nM
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[2,3-dichloro-4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]phenyl]urea	IC50	23 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	24 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[4-(hydroxymethyl)-3-methoxyphenyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	24 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[4-(methylsulfamoylmethyl)phenyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	29 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-(o-tolylamino)pyrimidin-4-yl)oxy) naphthalen-1-yl)urea	IC50	33 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-tert-butyl-1-[4-(hydroxymethyl)phenyl]pyrazol-5-yl]-3-[2,3-dichloro-4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea	IC50	35 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((4-hydroxy-2-methylphenyl) amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea	IC50	36 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[1-(4-methylphenyl)-3-propan-2-ylpyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	39 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(5-methylthiophen-2-yl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	41 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	43 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[6-(hydroxymethyl)-3-pyridinyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	44 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	45 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-hydroxyphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	45 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylsulfonylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	47 nM	US-8933228: Respiratory formulations and compounds for use therein
3-[2-(cyclopropanecarbonylamino)-[1,3]thiazolo[5,4-b]pyridin-5-yl]-N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	KD	57 nM	US-8765747: Fused 2-aminothiazole compounds
1-[4-(2-anilinopyrimidin-4-yl)oxynaphthalen-1-yl]-3-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]urea	IC50	60 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H- pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl) amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea	IC50	60 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-[(2-oxo-1,7a-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	67 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-fluoro-4-hydroxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	68 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	72 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(2-oxo-1,7a-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	74 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylsulfanylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	74 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((4-hydroxy-3-methoxyphenyl) amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea	IC50	77 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((4-methoxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	83 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-tert-butyl-1-(3,4-dichlorophenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	89 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-methylidene-3-oxopyrido[2,3-b]pyrazin-8-yl)oxynaphthalen-1-yl]urea	IC50	99 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-(2-methylidene-3-oxopyrido[2,3-b]pyrazin-8-yl)oxynaphthalen-1-yl]urea	IC50	100 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((3,4-dimethoxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	105 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-chloro-4-hydroxyphenyl) amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea	IC50	118 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(2-oxo-1,3,3a,4,5,6,7,7a-octahydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	119 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((3-methoxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	119 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-tert-butyl-1-(6-methoxy-3-pyridinyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	126 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((4-chloro-2-methylphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	133 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
N-[4-[4-[[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]acetamide	IC50	146 nM	US-9260410: P38 MAP kinase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2,4-dimethoxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	151 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3- (4-((2-((3-fluorophenyl)amino)pyrimidin- 4- yl)oxy)naphthalen-1-yl)urea	IC50	155 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-methoxyphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	161 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-chlorophenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	161 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	164 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-fluorophenyl)amino)pyrimidin- 4-yl)oxy)naphthalen-1-yl)urea	IC50	165 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-(tert-butyl)-1-(p-tolyl)-lH-pyrazol-5-yl)- 3-(4-((2-(m-tolylamino)pyrimidin-4-yl)oxy) naphthalen-1-yl)urea	IC50	169 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors

ChEMBL bioactivities

1184 potent at pChembl≥5 of 1243 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
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
9.40	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	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
9.16	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
9.09	IC50	0.82	nM	CHEMBL1738839
9.04	IC50	0.91	nM	CHEMBL325211
9.01	Ki	0.97	nM	CHEMBL383137
9.01	IC50	0.97	nM	CHEMBL446404
9.00	IC50	1	nM	CHEMBL3220550
9.00	Kd	1	nM	CHEMBL420047
8.96	IC50	1.1	nM	CHEMBL358108
8.96	IC50	1.1	nM	CHEMBL142463
8.92	IC50	1.2	nM	CHEMBL92648
8.92	IC50	1.2	nM	CHEMBL4227523
8.89	IC50	1.3	nM	CHEMBL356754

PubChem BioAssay actives

921 with measured affinity, of 3527 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-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
4-[3-methyl-2-piperidin-4-yl-5-[3-(trifluoromethyl)phenyl]imidazol-4-yl]-N-[(1S)-1-phenylethyl]pyridin-2-amine	127243: Inhibition of Mitogen-activated protein kinase p38	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
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
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
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
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
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0013	uM
1-(2,6-dichlorophenyl)-6-(2,4-difluorophenyl)sulfanyl-7-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-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	0.0013	uM
N,N,N’-trimethyl-N’-[5-[2-[[(1S)-1-phenylethyl]amino]pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]pyridazin-3-yl]ethane-1,2-diamine	127106: Inhibition of Mitogen-activated protein kinase p38	ic50	0.0014	uM
2-(4-fluorophenyl)-4-[(3-methoxyphenyl)methoxy]-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	0.0015	uM
3-[[2-amino-5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-N-(2-ethylpyrazol-3-yl)-4-methylbenzamide	254526: Binding affinity for human p38 MAP kinase expressed in Escherichia coli using [gamma-33P]ATP; n=4	ki	0.0015	uM
1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2-one	274335: Inhibition of p38	ic50	0.0015	uM
7-(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	0.0015	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	increases phosphorylation, decreases expression, increases expression, increases activity	3
Cannabidiol	decreases expression	3
bisphenol A	affects expression, increases expression	2
cobaltous chloride	decreases expression	2
pirfenidone	decreases reaction, increases reaction, decreases phosphorylation, increases phosphorylation, increases expression (+2 more)	2
Vorinostat	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, affects expression	2
Cisplatin	affects cotreatment, increases expression	2
Copper	affects binding, decreases expression	2
Cadmium Chloride	increases phosphorylation, increases expression, decreases expression, increases abundance	2
ON123300	increases phosphorylation	1
pradimicin-IRD	affects expression, affects response to substance	1
bufotalin	increases expression	1
myristicin	decreases expression	1
bis(tri-n-butyltin)oxide	decreases expression	1
deoxynivalenol	decreases expression	1
tributyltin	decreases expression	1
afimoxifene	decreases response to substance	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
ochratoxin A	decreases expression	1
methylmercury II	decreases expression	1
glycidamide	increases expression	1
SB 203580	decreases expression	1
xanthohumol	decreases phosphorylation	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
obeticholic acid	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

872 unique, capped per target: 815 binding, 55 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

6 cell lines: 4 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3AN	Abcam HEK293T MAPK12 KO	Transformed cell line	Female
CVCL_D7UJ	Ubigene A-549 MAPK12 KO	Cancer cell line	Male
CVCL_D8Q5	Ubigene HCT 116 MAPK12 KO	Cancer cell line	Male
CVCL_D9JM	Ubigene HEK293 MAPK12 KO	Transformed cell line	Female
CVCL_E0HG	Ubigene HeLa MAPK12 KO	Cancer cell line	Female
CVCL_SW86	HAP1 MAPK12 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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