MAPK3

Summary

MAPK3 (mitogen-activated protein kinase 3, HGNC:6877) is a protein-coding gene on chromosome 16p11.2, encoding Mitogen-activated protein kinase 3 (P27361). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described.

Source: NCBI Gene 5595 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 61 total — 2 pathogenic, 1 likely-pathogenic
• Druggable target: yes — 30 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002746

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6877
Approved symbol	MAPK3
Name	mitogen-activated protein kinase 3
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	ERK1, p44mapk, p44erk1, ERK-1
Ensembl gene	ENSG00000102882
Ensembl biotype	protein_coding
OMIM	601795
Entrez	5595

Gene structure

Transcript identifiers

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

ENST00000263025, ENST00000322266, ENST00000395199, ENST00000395200, ENST00000395202, ENST00000461737, ENST00000466521, ENST00000473431, ENST00000478356, ENST00000481230, ENST00000483869, ENST00000484663, ENST00000485579, ENST00000490298, ENST00000494643, ENST00000894952, ENST00000968148

RefSeq mRNA: 3 — MANE Select: NM_002746 NM_001040056, NM_001109891, NM_002746

CCDS: CCDS10672, CCDS42148, CCDS42149

Canonical transcript exons

ENST00000263025 — 9 exons

Exon	Start	End
ENSE00000678746	30118047	30118163
ENSE00000678748	30117154	30117285
ENSE00001899118	30114105	30114708
ENSE00003484640	30118349	30118538
ENSE00003527152	30116636	30116790
ENSE00003571899	30121824	30122006
ENSE00003588092	30117670	30117784
ENSE00003656423	30116894	30117003
ENSE00003842489	30123040	30123220

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1314 / max 164.0738, expressed in 1803 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157030	18.9872	1794
157026	1.0146	613
157029	0.7717	523
157028	0.7529	491
157027	0.5968	343
157023	0.0082	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.79	gold quality
lower esophagus mucosa	UBERON:0035834	98.65	gold quality
mucosa of transverse colon	UBERON:0004991	98.55	gold quality
amygdala	UBERON:0001876	98.30	gold quality
cingulate cortex	UBERON:0003027	98.27	gold quality
anterior cingulate cortex	UBERON:0009835	98.22	gold quality
transverse colon	UBERON:0001157	98.13	gold quality
mucosa of stomach	UBERON:0001199	98.01	gold quality
nucleus accumbens	UBERON:0001882	97.93	gold quality
ectocervix	UBERON:0012249	97.86	gold quality
rectum	UBERON:0001052	97.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.78	gold quality
gall bladder	UBERON:0002110	97.64	gold quality
endocervix	UBERON:0000458	97.63	gold quality
body of uterus	UBERON:0009853	97.52	gold quality
prefrontal cortex	UBERON:0000451	97.51	gold quality
caudate nucleus	UBERON:0001873	97.47	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.46	gold quality
omental fat pad	UBERON:0010414	97.45	gold quality
peritoneum	UBERON:0002358	97.42	gold quality
right ovary	UBERON:0002118	97.39	gold quality
right coronary artery	UBERON:0001625	97.38	gold quality
putamen	UBERON:0001874	97.29	gold quality
right uterine tube	UBERON:0001302	97.28	gold quality
left ovary	UBERON:0002119	97.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.25	gold quality
esophagus mucosa	UBERON:0002469	97.24	gold quality
small intestine	UBERON:0002108	97.12	gold quality
left uterine tube	UBERON:0001303	97.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.29
E-MTAB-7303	no	427.36

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
SOX9	Unknown
SULT1A1	Activation
SULT1A3	Activation

Upstream regulators (CollecTRI, top): AP1, DLL4, GFI1, MT3, MYC, NFATC1, PDCD10, SOX9, STAT3, TP53, TWIST1, ZHX2, ZNF236

Literature-anchored findings (GeneRIF, showing 40)

• MEK1 interacts with ERK1. This interaction is mediated via a conserved N-terminal docking site in MEK1. (PMID:11134045)
• Unregulated activation of STAT-5, ERK1/2 and c-Fos may contribute to the phenotypic transformation from myelodysplastic syndrome to acute leukaemia. Impaired ERK1/2 signalling pathways were activated only by GM-CSF but not by Epo. (PMID:11583024)
• role in acidic extracellular pH in inducing VEGF in human glioblastoma cells (PMID:11741977)
• Extracellular signal-regulated kinase (ERK1 and ERK2) activation is required for GP Ibalpha-dependent endothelial cell migration. (PMID:11776327)
• CD40 ligation induces macrophage IL-10 and TNF-alpha production: differential use of the PI3K and p42/44 MAPK-pathways. (PMID:11792123)
• p42/44MAPK regulates baseline permeability and cGMP-induced hyperpermeability in endothelial cells (PMID:11866540)
• role of activation in TFF-peptide-stimulated bronchial epithelial cell migration and tumor necrosis factor-alpha-induced interleukin-6 and IL-8 secretion (PMID:11884401)
• ML-1-induced IL-6 and IL-8 production is mediated through the activation of ERK1/2 (PMID:11891214)
• role of activation in IGFBP-5 stimulation of growth and IGF-I secretion in intestinal smooth muscle (PMID:11923300)
• Protease activity, growth factor-like and kringle domains of uPA differentially contribute to activation of p42/p44erk1,2 and p38 MAP-kinases. (PMID:11930938)
• Activation of the p44 MAPK pathway contributes to the underlying mechanism of IL-12 suppression by soluble CD40 ligand. (PMID:11937531)
• Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. (PMID:11952164)
• Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta (PMID:11960991)
• eNOS expression might be regulated by PI-3K and the ERK1/2 signaling pathway (PMID:11961297)
• Eicosapentaenoic acid and docosahexaenoic acid modulate MAP kinase enzyme activity in human T-cells (PMID:12030372)
• ERK1 activity ad dual-phosphorylation were undetectable in expanding and self-renewing hematopoietic progenitors (HP). Adding IL-3, inducing maturation and cell death in HP, led to sustained high levels of ERK1 activity and dual-phosphorylation. (PMID:12032872)
• Provant Wound Closure System induces activation of p44/42 MAP kinase in normal cultured human fibroblasts (PMID:12081892)
• ERK activation by cAMP does not require RAP1 (PMID:12082090)
• Control of mycobacterial replication in human macrophages: roles of extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinase pathways. (PMID:12183542)
• ITGB1 activated by ERK1/2, p38 MAPK after hypoxia (PMID:12200131)
• connective tissue growth factor induced fibronectin production, cell migration, and cytoskeletal rearrangement are associated with recruitment of Src and phosphorylation of p42/44 MAPK and protein kinase B (PMID:12218048)
• EPO induces long-lasting phosphorylation of MAPK p42/44 in vascular endothelial cells, activating signal pathways increasing the thrombogenicity of their extracellular matrices. (PMID:12362243)
• expression of extracellular signal-regulated kinase, ERK1, and its relationship with clinicopathological characteristics of breast cancer (PMID:12408764)
• LMP1 inhibits transforming growth factor-beta 1-mediated induction of MAPK/p21 in Epstein-barr virus infected gastric epithelial cell line GT38 (PMID:12441075)
• report the activation of the extracellular signal-regulated kinases (ERKs) 1 and 2 (p44 and p42 MAP kinase) through the human serotonin receptors 5-HT(4(b)) and 5-HT(7(a)) (PMID:12446729)
• Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways (PMID:12456688)
• Decreased phosphorylation of protein kinase B and erk1/erk2 in neutrophils from patients with myelodysplastic syndrome (PMID:12529294)
• Data show that p-MEK1/2 and p-ERK1/2 are present in neurons in the initial stages of neurofibrillary degeneration in Alzheimer’s disease, before deposition of beta-amyloid. (PMID:12531514)
• Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. (PMID:12538349)
• Helicobacter pylori-induced ERK1 activation, especially by the cagA(+) strain, may play a protective role against gastric epithelial cell apoptosis partially through maintenance of bcl-2 gene expression (PMID:12540563)
• inhibition amplifies ajoene-induced cell death in human promyeloleukemic cells (PMID:12555071)
• pp90RSK- and protein kinase C-dependent pathway regulates p42/44MAPK-induced LDL receptor transcription in HepG2 cells. (PMID:12562867)
• NiCl2 induced that of p44/42 extracellular signal-regulated kinases, p38, and stress-activated protein kinase/c-jun N-terminal kinases. (PMID:12603851)
• acute hyperglycemia-mediated mononuclear cell activation is dependent on activation of ras, p42/p44 mitogen-activated protein kinase phosphorylation, and subsequent NF-kappaB activation (PMID:12606501)
• HDL induced a potent signal through a Ras/MAPK pathway mediated by a pertussis toxin-sensitive G-protein coupled receptor to the angiogenic phenotype in HCECs. (PMID:12637339)
• stretch of airway smooth muscle causes production of interleukin-8 by activating CCAAT/enhancer-binding protein and activator protein-1 transcription factor through activation of extracellular regulated kinase-1 and 2 and p38 kinase signaling pathways (PMID:12637525)
• EGF & ionizing radiation up-regulate the DNA repair genes XRCC1 & ERCC1 in DU145 & LNCaP prostate carcinoma, showing a complex control of DNA repair activation that may be more generally dependent on MAPK (ERK1/2) signaling than previously noted. (PMID:12643788)
• p38 and ERK1/2 have roles in coordinating cellular migration and proliferation in epithelial wound healing (PMID:12663671)
• ERK1 is activated in a pathway that involves MKP1 and ubiquitin-proteasome (PMID:12676937)
• The 1,25(OH)(2)D3-responsive element in cystatin A gene is identical to TRE, T2 (-272 to -278). Suppression of Raf-1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of normal human keratinocytes. (PMID:12682854)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk3	ENSDARG00000070573
mus_musculus	Mapk3	ENSMUSG00000063065
rattus_norvegicus	Mapk3	ENSRNOG00000053583
rattus_norvegicus		ENSRNOG00000067941
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), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Mitogen-activated protein kinase 3 — P27361 (reviewed: P27361)

Alternative names: ERT2, Extracellular signal-regulated kinase 1, Insulin-stimulated MAP2 kinase, MAP kinase isoform p44, Microtubule-associated protein 2 kinase, p44-ERK1

All UniProt accessions (9): P27361, A1QJE5, E9PBK7, E9PJF0, E9PQW4, E9PRH7, H0YDH9, H0YEX6, L7RXH5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade also plays a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DEPTOR, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Phosphorylates GJA1 at ‘Ser-279’ and ‘Ser-282’ resulting in an increase in GJA1 ubiquitination and ultimately lysosomal degradation.

Subunit / interactions. Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, and SGK1. Interacts with PEA15 and MKNK2. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Interacts with TPR. Interacts with CDKN2AIP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock. Interacts with CAVIN4. Interacts with GIT1; this interaction is necessary for MAPK3 localization to focal adhesions. Interacts with ZNF263. Interacts with EBF4. (Microbial infection) Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine-kinase activity.

Subcellular location. Cytoplasm. Nucleus. Membrane. Caveola. Cell junction. Focal adhesion.

Post-translational modifications. Phosphorylated upon KIT and FLT3 signaling. Dually phosphorylated on Thr-202 and Tyr-204, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-204. Ubiquitinated by TRIM15 via ‘Lys-63’-linked ubiquitination; leading to activation. Deubiquitinated by CYLD.

Activity regulation. Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-202 and Tyr-204 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.

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 (3)

UniProt ID	Names	Canonical?
P27361-1	1	yes
P27361-2	2
P27361-3	3, ERK1b

RefSeq proteins (3): NP_001035145, NP_001103361, NP_002737* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003527	MAP_kinase_CS	Conserved_site
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR008349	MAPK_ERK1/2	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 (54 total): helix 20, strand 10, modified residue 5, turn 5, splice variant 2, mutagenesis site 2, binding site 2, initiator methionine 1, chain 1, sequence variant 1, sequence conflict 1, domain 1, region of interest 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4QTB	X-RAY DIFFRACTION	1.4
6GES	X-RAY DIFFRACTION	2.07
9TU0	X-RAY DIFFRACTION	2.17
2ZOQ	X-RAY DIFFRACTION	2.39
9UUX	ELECTRON MICROSCOPY	3.12
9UW4	ELECTRON MICROSCOPY	3.2
9UUR	ELECTRON MICROSCOPY	3.36
9UW3	ELECTRON MICROSCOPY	3.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27361-F1	89.09	0.76

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): 166 (proton acceptor)

Ligand- & substrate-binding residues (2): 48–56; 71

Post-translational modifications (5): 202, 204, 207, 2, 198

Mutagenesis-validated functional residues (2):

Position	Phenotype
168	complete loss of ubiquitination by trim15; when associated with r-302.
302	complete loss of ubiquitination by trim15; when associated with r-168.

Function

Pathways and Gene Ontology

Reactome pathways

163 pathways

ID	Pathway
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112409	RAF-independent MAPK1/3 activation
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-1181150	Signaling by NODAL
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-1502540	Signaling by Activin
R-HSA-170968	Frs2-mediated activation
R-HSA-198753	ERK/MAPK targets
R-HSA-202670	ERKs are inactivated
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-444257	RSK activation
R-HSA-445144	Signal transduction by L1
R-HSA-450341	Activation of the AP-1 family of transcription factors
R-HSA-456926	Thrombin signalling through proteinase activated receptors (PARs)
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5674135	MAP2K and MAPK activation

MSigDB gene sets: 966 (showing top): PID_BCR_5PATHWAY, GOBP_REGULATION_OF_GOLGI_ORGANIZATION, GOBP_CHROMOSOME_ORGANIZATION, BIOCARTA_PTEN_PATHWAY, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_AUTOPHAGY, BIOCARTA_FMLP_PATHWAY, PID_S1P_S1P1_PATHWAY, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, PID_TELOMERASE_PATHWAY

GO Biological Process (70): MAPK cascade (GO:0000165), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), DNA-templated transcription (GO:0006351), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), cell surface receptor signaling pathway (GO:0007166), epidermal growth factor receptor signaling pathway (GO:0007173), insulin receptor signaling pathway (GO:0008286), positive regulation of macrophage chemotaxis (GO:0010759), Schwann cell development (GO:0014044), phosphorylation (GO:0016310), sensory perception of pain (GO:0019233), regulation of ossification (GO:0030278), BMP signaling pathway (GO:0030509), obsolete regulation of cellular pH (GO:0030641), thyroid gland development (GO:0030878), positive regulation of cyclase activity (GO:0031281), lipopolysaccharide-mediated signaling pathway (GO:0031663), positive regulation of telomere maintenance (GO:0032206), regulation of stress-activated MAPK cascade (GO:0032872), cellular response to amino acid starvation (GO:0034198), intracellular signal transduction (GO:0035556), peptidyl-tyrosine autophosphorylation (GO:0038083), ERBB2-ERBB3 signaling pathway (GO:0038133), outer ear morphogenesis (GO:0042473), myelination (GO:0042552), signal transduction in response to DNA damage (GO:0042770), response to exogenous dsRNA (GO:0043330), positive regulation of transcription by RNA polymerase II (GO:0045944), insulin-like growth factor receptor signaling pathway (GO:0048009), thymus development (GO:0048538), modulation of chemical synaptic transmission (GO:0050804), cartilage development (GO:0051216), stress-activated MAPK cascade (GO:0051403), regulation of cytoskeleton organization (GO:0051493), Bergmann glial cell differentiation (GO:0060020), face development (GO:0060324), lung morphogenesis (GO:0060425), trachea formation (GO:0060440), cardiac neural crest cell development involved in heart development (GO:0061308)

GO Molecular Function (13): phosphotyrosine residue binding (GO:0001784), protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), phosphatase binding (GO:0019902), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), DNA-binding transcription factor binding (GO:0140297), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (22): nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), caveola (GO:0005901), focal adhesion (GO:0005925), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), pseudopodium (GO:0031143), ciliary basal body (GO:0036064), ciliary tip (GO:0097542), glutamatergic synapse (GO:0098978), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-21 pathways:

Category	Pathways
Cellular Senescence	3
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
RAF-independent MAPK1/3 activation	1
MAPK1/MAPK3 signaling	1
Antimicrobial mechanism of IFN-stimulated genes	1
Developmental Biology	1
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Signaling by TGFB family members	1
Prolonged ERK activation events	1
Nuclear Events (kinase and transcription factor activation)	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
ERK/MAPK targets	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membrane-bounded organelle	3
cytoplasm	3
protein kinase activity	2
endomembrane system	2
endosome	2
plasma membrane bounded cell projection	2
cilium	2
intracellular signaling cassette	1
T cell mediated immune response to tumor cell	1
negative regulation of T cell mediated immunity	1
negative regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
gene expression	1
RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
signal transduction	1
ERBB signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
positive regulation of leukocyte chemotaxis	1
regulation of macrophage chemotaxis	1
macrophage chemotaxis	1
regulation of granulocyte chemotaxis	1
positive regulation of macrophage migration	1
Schwann cell differentiation	1
glial cell development	1
phosphate-containing compound metabolic process	1
sensory perception	1
ossification	1
regulation of multicellular organismal process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
endocrine system development	1
gland development	1
cyclase activity	1

Protein interactions and networks

STRING

9970 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK3	MAP2K1	Q02750	975
MAPK3	TNF	P01375	921
MAPK3	FOS	P01100	907
MAPK3	ARRB2	P32121	892
MAPK3	ARRB1	P49407	883
MAPK3	CREB1	P16220	876
MAPK3	NFKB1	P19838	875
MAPK3	TP53	P04637	871
MAPK3	STAT3	P40763	867
MAPK3	CTNNB1	P35222	866
MAPK3	IL1B	P01584	859
MAPK3	CASP3	P42574	858
MAPK3	BCL2	P10415	853
MAPK3	PXN	P49023	853
MAPK3	IFNG	P01579	846
MAPK3	PXDN	Q92626	846

IntAct

265 interactions, top by confidence:

A	B	Type	Score
MAPK3	DHPS	psi-mi:“MI:0915”(physical association)	0.920
MAPK1	MAPK3	psi-mi:“MI:0914”(association)	0.770
MAPK3	MAPK1	psi-mi:“MI:0914”(association)	0.770
MAPK3	PEA15	psi-mi:“MI:0915”(physical association)	0.740
DUSP6	MAPK3	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAPK3	DUSP1	psi-mi:“MI:2364”(proximity)	0.710
RPS6KA3	ROCK2	psi-mi:“MI:0914”(association)	0.640
MAPK3	MAPK3	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
DAPK1	MAPK3	psi-mi:“MI:0915”(physical association)	0.620
MAPK3	DAPK1	psi-mi:“MI:0915”(physical association)	0.620
DUSP9	MAPK3	psi-mi:“MI:2364”(proximity)	0.610
UNG	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
FAM135B	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
PADI3	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
CD248	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
KLHL32	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
MRFAP1L1	MAPK3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (558): MAPK3 (Affinity Capture-Western), STAR (Reconstituted Complex), STAR (Biochemical Activity), MAPK3 (Affinity Capture-Western), MAPK3 (Biochemical Activity), RAF1 (Affinity Capture-Western), MAP2K1 (Affinity Capture-Western), MAPK1 (Affinity Capture-Western), MAPK3 (Affinity Capture-Western), MAPK3 (Affinity Capture-Western), ZC3HC1 (Biochemical Activity), CREBBP (Biochemical Activity), MAPK3 (Biochemical Activity), DHPS (Affinity Capture-MS), MAPK3 (Affinity Capture-Western)

ESM2 similar proteins: A0A5B9GBF0, A1CPG7, A1D2C9, A1IVT7, A2BD05, A2QRF6, B0XR80, D3ZBE5, G1XJZ4, G5EDF7, G5EFM9, M1T7M3, O09110, O75716, O88697, P0CP69, P21708, P26696, P27361, P28482, P45985, P46196, P46734, P47809, P52564, P57760, P59895, P70236, Q0D0P5, Q0U4L8, Q1DUU8, Q1KTF2, Q2WFL5, Q4PC06, Q4W6D3, Q4WSF6, Q52PH6, Q56R42, Q5E9X2, Q63844

Diamond homologs: A0A194WDG1, A0A1S3Z5Y0, A1CPG7, A1D2C9, A2QRF6, A2XFC8, A5PKJ4, A9S9Q8, A9T142, B0XR80, B0Y4X4, B0Y8W7, C4YGK0, G4N0Z0, G4N374, O13352, O23236, O42781, O61443, O94737, P0C865, P0CP66, P0CP67, P0CP68, P0CP69, P14681, P16892, P21708, P26696, P27361, P27638, P28482, P36005, P39745, P40417, P42525, P43068, P46196, P47811, P47812

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
MAPK3	up-regulates	TP53	phosphorylation
PTPRJ	down-regulates	MAPK3	dephosphorylation
MAPK3	“down-regulates activity”	CASP9	phosphorylation
MAPK3	up-regulates	SMAD4	phosphorylation
MAPK3	“down-regulates activity”	THRB	phosphorylation
MAPK3	“up-regulates activity”	RPS6KA1	phosphorylation
DUSP3	“down-regulates activity”	MAPK3	dephosphorylation
DUSP6	down-regulates	MAPK3	dephosphorylation
PPP1CA	down-regulates	MAPK3	dephosphorylation
PPP2CA	down-regulates	MAPK3	dephosphorylation
PTPRB	up-regulates	MAPK3	dephosphorylation
MAPK3	“down-regulates activity”	HNRNPK	phosphorylation
MAPK3	“up-regulates activity”	HSPB8	phosphorylation
PEA15	down-regulates	MAPK3
MAPK3	down-regulates	UBTF	phosphorylation
MAPK3	up-regulates	MAZ	phosphorylation
MAPK3	down-regulates	TAL1	phosphorylation
MAPK3	up-regulates	SP1	phosphorylation
MAPK3	up-regulates	ETS1	phosphorylation
MAPK3	“up-regulates activity”	FOS	phosphorylation
MAPK3	up-regulates	SPHK1	phosphorylation
MAPK3	up-regulates	STAT3	phosphorylation
MAPK3	up-regulates	NCKIPSD	phosphorylation
MAPK3	down-regulates	POLR2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 192 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
RAF-independent MAPK1/3 activation	5	22.7×	8e-04
Negative regulation of MAPK pathway	8	15.2×	4e-05
Nuclear Events (kinase and transcription factor activation)	6	14.8×	8e-04
Signaling by RAF1 mutants	6	11.9×	1e-03
Signaling by high-kinase activity BRAF mutants	5	11.3×	5e-03
Signaling by moderate kinase activity BRAF mutants	6	10.9×	1e-03
Paradoxical activation of RAF signaling by kinase inactive BRAF	6	10.9×	1e-03
Signaling downstream of RAS mutants	6	10.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein dephosphorylation	9	11.7×	1e-04
negative regulation of ERK1 and ERK2 cascade	7	8.9×	3e-03
MAPK cascade	9	8.1×	7e-04
protein phosphorylation	14	5.6×	1e-04
in utero embryonic development	12	5.1×	2e-03
negative regulation of apoptotic process	16	3.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	30
Likely benign	12
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1176677	GRCh37/hg19 16p11.2(chr16:29675050-30218221)x1	Pathogenic
997070	GRCh37/hg19 16p11.2(chr16:29652999-30198600)	Pathogenic
2576026	NM_002746.3(MAPK3):c.443A>G (p.Tyr148Cys)	Likely pathogenic

SpliceAI

1780 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30116631:CTCA:C	donor_loss	1.0000
16:30116632:TCACC:T	donor_loss	1.0000
16:30116633:CA:C	donor_loss	1.0000
16:30116634:A:AC	donor_gain	1.0000
16:30116634:A:C	donor_loss	1.0000
16:30116635:C:CC	donor_gain	1.0000
16:30116635:C:CG	donor_loss	1.0000
16:30116635:CCAGG:C	donor_gain	1.0000
16:30116787:CTGG:C	acceptor_gain	1.0000
16:30116788:TGG:T	acceptor_gain	1.0000
16:30116789:GG:G	acceptor_gain	1.0000
16:30116790:GC:G	acceptor_loss	1.0000
16:30116791:C:CC	acceptor_gain	1.0000
16:30116791:CT:C	acceptor_loss	1.0000
16:30116796:G:C	acceptor_gain	1.0000
16:30116796:G:GC	acceptor_gain	1.0000
16:30116799:G:C	acceptor_gain	1.0000
16:30116889:CCCA:C	donor_loss	1.0000
16:30116891:CAC:C	donor_loss	1.0000
16:30116892:A:AG	donor_loss	1.0000
16:30116893:C:CG	donor_loss	1.0000
16:30116999:AAGGG:A	acceptor_gain	1.0000
16:30117000:AGGG:A	acceptor_gain	1.0000
16:30117001:GGG:G	acceptor_gain	1.0000
16:30117001:GGGCT:G	acceptor_loss	1.0000
16:30117002:GG:G	acceptor_gain	1.0000
16:30117002:GGC:G	acceptor_loss	1.0000
16:30117004:C:CC	acceptor_gain	1.0000
16:30117004:CTATG:C	acceptor_loss	1.0000
16:30117006:A:AC	acceptor_gain	1.0000

AlphaMissense

2471 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:30117684:A:G	L254P	1.000
16:30117705:C:A	G247V	1.000
16:30117705:C:T	G247D	1.000
16:30117706:C:G	G247R	1.000
16:30117746:G:C	C233W	1.000
16:30117747:C:T	C233Y	1.000
16:30117748:A:G	C233R	1.000
16:30117750:C:T	G232D	1.000
16:30117751:C:G	G232R	1.000
16:30117758:C:A	W229C	1.000
16:30117758:C:G	W229C	1.000
16:30117760:A:G	W229R	1.000
16:30117760:A:T	W229R	1.000
16:30117765:T:A	D227V	1.000
16:30117765:T:G	D227A	1.000
16:30117766:C:A	D227Y	1.000
16:30117766:C:G	D227H	1.000
16:30118069:G:T	P213Q	1.000
16:30118075:C:G	R211P	1.000
16:30118079:A:G	Y210H	1.000
16:30118082:A:G	W209R	1.000
16:30118082:A:T	W209R	1.000
16:30118085:G:T	R208S	1.000
16:30118090:G:T	A206D	1.000
16:30118097:A:G	Y204H	1.000
16:30118144:G:T	A188D	1.000
16:30118147:A:G	L187P	1.000
16:30118150:C:T	G186D	1.000
16:30118151:C:G	G186R	1.000
16:30118155:A:C	D184E	1.000

dbSNP variants (sampled 300 via entrez): RS1000319102 (16:30122938 G>A,T), RS1000539202 (16:30123413 C>A,G,T), RS1000548119 (16:30115735 C>G,T), RS1000906404 (16:30118001 C>T), RS1000919414 (16:30116280 C>T), RS1001438896 (16:30123879 T>G), RS1001532297 (16:30123513 C>G), RS1001752978 (16:30123768 C>A,T), RS1002332244 (16:30118626 ACCT>A), RS1003206253 (16:30124984 T>A,C), RS1003998795 (16:30113964 T>G), RS1004294823 (16:30114227 G>A), RS1004683414 (16:30114078 G>A,T), RS1004770156 (16:30118933 G>C,T), RS1004787323 (16:30120943 C>G)

Disease associations

OMIM: gene MIM:601795 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001875_1	Pubertal anthropometrics	9.000000e-11
GCST002539_82	Schizophrenia	5.000000e-11
GCST003995_34	Tonsillectomy	4.000000e-08
GCST004521_236	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST004946_142	Schizophrenia	8.000000e-13
GCST005014_42	Tonsillectomy	4.000000e-08
GCST005531_11	Multiple sclerosis	2.000000e-11
GCST006585_2681	Blood protein levels	5.000000e-06
GCST006803_23	Schizophrenia	6.000000e-13
GCST007062_5	Hodgkin’s lymphoma	4.000000e-08
GCST008151_77	Waist circumference	4.000000e-08
GCST008152_103	Weight	4.000000e-06
GCST008160_30	Waist circumference	4.000000e-08
GCST009597_219	Multiple sclerosis	3.000000e-06
GCST010703_269	Brain morphology (MOSTest)	4.000000e-13
GCST90002409_34	Childhood body mass index	2.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0004338	body weight
EFO:0004346	neuroimaging measurement
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1907606 (PROTEIN FAMILY), CHEMBL3385 (SINGLE PROTEIN), CHEMBL4523619 (PROTEIN FAMILY), CHEMBL6195573 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

30 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 574,174 (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
CHEMBL11359	CISPLATIN	4
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL267495	NALFURAFINE	4	310
CHEMBL496	HEXACHLOROPHENE	4	26,164
CHEMBL506247	TANNIC ACID	4	25,753
CHEMBL584	NELFINAVIR	4	36,859
CHEMBL603	ZAFIRLUKAST	4	23,220
CHEMBL727	THIOGUANINE	4	294,612
CHEMBL964	DISULFIRAM	4	38,611
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL1630578	TIRILAZAD	3	1,197
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL508338	THIMEROSAL	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL3544964	RAVOXERTINIB	2	1,243
CHEMBL3590106	ULIXERTINIB	2	1,495
CHEMBL475251	R-406	2	762
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL1950289	TANZISERTIB	2	419
CHEMBL460499	CARMOFUR	2
CHEMBL4650285	TEMUTERKIB	2
CHEMBL86754	IODOQUINOL	2
CHEMBL4482864	TIZATERKIB	1
CHEMBL4858364	MRTX-1133	1
CHEMBL1230607	PHA-793887	1
CHEMBL3128043	PF-03758309	1
CHEMBL4213970	MK-8353	1
CHEMBL4650280	ASN007	1
CHEMBL4650284	KO-947	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — ERK subfamily

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

Ligand	Action	Affinity	Parameter
ulixertinib	Inhibition	9.52	pIC50
sonvuterkib	Inhibition	8.85	pIC50
ravoxertinib	Inhibition	8.48	pIC50
MK-8353	Inhibition	7.64	pIC50
ERK inhibitor II	Inhibition	6.39	pKi

Binding affinities (BindingDB)

165 measured of 381 human assays (381 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
(5R)-2-[3-(2-methyl-4-pyridinyl)-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl]-7-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2,7-diazaspiro[4.4]nonan-1-one	IC50	150 nM	US-10493060
(5S)-7-[2-[4-[3-(1-methyl-1,2,4-triazol-3-yl)-1-bicyclo[1.1.1]pentanyl]piperidin-1-yl]-2-oxoethyl]-2-[3-(6-propan-2-yloxy-3-pyridinyl)-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl]-2,7-diazaspiro[4.4]nonan-1-one	IC50	150 nM	US-10493060
N-[2-[[2-[(4-hydroxycyclohexyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-methoxy-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexane-1-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-(2-hydroxyethoxy)-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexane-1-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[5-fluoro-2-[[2-[(4-fluorocyclohexyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(1-formylpiperidin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(1-acetylpiperidin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexane-1-carboxylic acid	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
4-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexane-1-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-acetylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]-3-chloropropanamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
3-chloro-N-[2-[[2-[[(3S)-1-(2-hydroxyacetyl)piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]propanamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
(1S,2S,3R,4R)-3-[[2-[[(3S)-1-acetylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-acetylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]-2-chloroacetamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[(1R,2R)-2-[[2-[[(3S)-1-(2-chloroacetyl)piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[(1R,2R)-2-[[2-[[(3S)-1-(2-hydroxyacetyl)piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]prop-2-ynamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
2-chloro-N-[(1R,2R)-2-[[2-[[(3S)-1-(2-hydroxyacetyl)piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]acetamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[4-methyl-2-[[2-[(4-oxocyclohexyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-[(2S)-2,3-dihydroxypropanoyl]piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-[(2R)-2,3-dihydroxypropanoyl]piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-oxaldehydoylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-acetylpyrrolidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-(2-hydroxyacetyl)pyrrolidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[(3S)-1-methylsulfonylpyrrolidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
5-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-3-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N,4-dimethoxy-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
4-cyano-N-methoxy-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-(2-hydroxyethoxy)-4-methyl-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-(2-hydroxyethoxy)-4-methoxy-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
4-cyano-N-(2-hydroxyethoxy)-3-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
4-methyl-3-[[4-[4-methyl-2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
2-fluoro-N,4-dimethyl-5-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
2-fluoro-N-(2-hydroxyethyl)-4-methyl-5-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
2-[[4-[2-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-4-carboxamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-(5-acetyl-2-methylanilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(2-methoxy-5-methyl-4-pyridinyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
3-[[4-[4-fluoro-2-(prop-1-en-2-ylsulfonylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-4-methylbenzamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[2-(4-ethylpiperazin-1-yl)-6-methoxy-4-pyridinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[[2-(4-acetylpiperazin-1-yl)-6-methoxy-4-pyridinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(2-methoxy-6-morpholin-4-yl-4-pyridinyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(2,6-dimethoxy-4-pyridinyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[5-chloro-2-[(4-methoxycyclohexyl)amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[5-chloro-2-[(4-hydroxycyclohexyl)amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[5-chloro-2-(cyclohexylamino)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(4-fluorocyclohexyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(1-acetylpiperidin-3-yl)amino]-5-chloropyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[2-[(1-acetylpiperidin-4-yl)amino]-5-chloropyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[5-chloro-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof
N-[2-[[5-chloro-2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide	IC50	300 nM	US-9796700: ERK inhibitors and uses thereof

ChEMBL bioactivities

537 potent at pChembl≥5 of 566 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL318804
9.89	IC50	0.13	nM	TIVOZANIB
9.26	EC50	0.55	nM	NALFURAFINE
9.19	Ki	0.65	nM	TEMUTERKIB
9.12	IC50	0.76	nM	CHEMBL5439556
8.92	IC50	1.2	nM	RAVOXERTINIB
8.82	IC50	1.5	nM	CHEMBL4434915
8.82	Kd	1.5	nM	ERKi
8.77	IC50	1.7	nM	TIZATERKIB
8.70	IC50	2	nM	ASN007
8.70	IC50	2	nM	CHEMBL5396786
8.64	IC50	2.3	nM	CHEMBL4212211
8.64	IC50	2.3	nM	MRTX-1133
8.60	IC50	2.5	nM	CHEMBL3590107
8.57	IC50	2.7	nM	CHEMBL3409588
8.56	IC50	2.75	nM	CHEMBL5070887
8.48	IC50	3.3	nM	CHEMBL4588783
8.47	IC50	3.4	nM	CHEMBL4440109
8.46	IC50	3.5	nM	CHEMBL4212211
8.44	IC50	3.6	nM	CHEMBL4567212
8.42	IC50	3.8	nM	CHEMBL4565958
8.41	IC50	3.9	nM	CHEMBL4571067
8.40	IC50	4	nM	CHEMBL3590107
8.39	IC50	4.1	nM	CHEMBL4532652
8.33	IC50	4.7	nM	CHEMBL4452853
8.30	IC50	5	nM	CHEMBL4436718
8.30	IC50	5	nM	TEMUTERKIB
8.30	IC50	5	nM	CHEMBL5430105
8.30	IC50	5	nM	CHEMBL5431126
8.24	IC50	5.7	nM	TIZATERKIB
8.22	IC50	6	nM	CHEMBL5414521
8.21	IC50	6.1	nM	RAVOXERTINIB
8.21	IC50	6.23	nM	CHEMBL5903840
8.15	IC50	7	nM	CHEMBL498344
8.15	IC50	7	nM	CHEMBL5422015
8.10	IC50	8	nM	CHEMBL3590107
8.10	IC50	7.9	nM	CHEMBL4209570
8.10	IC50	7.9	nM	CHEMBL4435650
8.10	IC50	8	nM	CHEMBL5424566
8.10	IC50	8	nM	CHEMBL5437468
8.05	IC50	9	nM	CHEMBL526479
8.05	IC50	9	nM	CHEMBL5437386
8.04	IC50	9.1	nM	CHEMBL4458562
8.00	EC50	10	nM	R-406
8.00	IC50	10	nM	CHEMBL4470113
8.00	IC50	10	nM	CHEMBL498674
8.00	IC50	10	nM	CHEMBL5183609
8.00	IC50	10	nM	KO-947
8.00	IC50	10	nM	CHEMBL5436095
8.00	IC50	10	nM	CHEMBL5409912

PubChem BioAssay actives

361 with measured affinity, of 2974 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[3-chloro-4-(1-methylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	102178: Inhibit ion of MAPK phosphorylation in LoVo cells	ic50	<0.0001	uM
Tivozanib	2159223: Inhibition of ERK1 phosphorylation in VEGF-stimulated serum-starved human HUVEC cells by immunoblotting analysis	ic50	0.0001	uM
N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-[5-chloro-2-(propan-2-ylamino)-4-pyridinyl]-1H-pyrrole-2-carboxamide	1896223: Binding affinity to ERK1 (unknown origin) measured after 20 mins in presence of [gamma33P]ATP by scintillation counter analysis	ki	0.0003	uM
6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one	1896229: Binding affinity to ERK1 (unknown origin)	ki	0.0006	uM
(E)-N-[(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-3-(furan-3-yl)-N-methylprop-2-enamide	1610005: Inhibition of ERK1 phosphorylation (unknown origin)	ec50	0.0006	uM
5-ethyl-6-fluoro-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0008	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one	1247138: Inhibition of ERK1 (unknown origin)	ic50	0.0012	uM
2-[1-(3-chlorophenyl)-2-hydroxyethyl]-6-[2-(oxan-4-ylamino)pyrimidin-4-yl]-3H-isoindol-1-one	1623576: Inhibition of ERK1 (unknown origin) using lipid as substrate after 40 mins by ADP-Glo luminescence assay	ic50	0.0015	uM
(6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0017	uM
N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-1-[5-methyl-2-(oxan-4-ylamino)pyrimidin-4-yl]imidazole-4-carboxamide	1896225: Inhibition of ERK1 (unknown origin)	ic50	0.0020	uM
(4R,7S,8S)-13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0020	uM
(2R)-2-[5-[5-chloro-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxo-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide	1375960: Inhibition of ERK1/2 phosphorylation in human A375 cells harboring BRAF V600E mutant after 4 hrs by ELISA	ic50	0.0023	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0023	uM
(3R)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0025	uM
2-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-6-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-1H-pyrrolo[1,2-c]imidazol-3-one	1827933: Inhibition of ERK1 (unknown origin) measured after 2 hr by ADP-glo assay	ic50	0.0027	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-(oxan-4-ylamino)pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0027	uM
2-[(3-chlorophenyl)methyl]-6-[2-(oxan-4-ylamino)pyrimidin-4-yl]-3H-isoindol-1-one	1623576: Inhibition of ERK1 (unknown origin) using lipid as substrate after 40 mins by ADP-Glo luminescence assay	ic50	0.0033	uM
(6S)-7-[(3,4-difluorophenyl)methyl]-6-methyl-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0034	uM
2-[1-(3-chlorophenyl)-2-hydroxyethyl]-6-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3H-isoindol-1-one	1623576: Inhibition of ERK1 (unknown origin) using lipid as substrate after 40 mins by ADP-Glo luminescence assay	ic50	0.0036	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(5-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0038	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methyl-4-pyridinyl)amino]pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0039	uM
2-[1-(3-chlorophenyl)-2-hydroxyethyl]-6-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3H-isoindol-1-one	1623576: Inhibition of ERK1 (unknown origin) using lipid as substrate after 40 mins by ADP-Glo luminescence assay	ic50	0.0041	uM
7-[(3-chlorophenyl)methyl]-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0047	uM
(5S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0050	uM
5-chloro-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0050	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0050	uM
(5S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]-3-fluorospiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0060	uM
3-chloro-4-cyclopropyl-5-[14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]phenol	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0070	uM
cis-(1S,3R)-3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclohexan-1-ol	362269: Inhibition of ERK1/2 phosphorylation in human MALME3M cells	ic50	0.0070	uM
(3S)-N-[3-(2-methoxy-4-pyridinyl)-1H-indazol-5-yl]-3-methylsulfanyl-1-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]pyrrolidine-3-carboxamide	1385274: Inhibition of ERK1 (unknown origin) using peptide substrate measured after 45 mins by IMAP assay	ic50	0.0079	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0079	uM
(5S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]-3-methoxyspiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0080	uM
(1S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0080	uM
(3S)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide	1800457: Selectivity screening from Article 10.1038/nchembio.1629: “A unique inhibitor binding site in ER K1/2 is associated with slow binding kinetics”	ic50	0.0083	uM
(NE)-N-[5-(1-piperidin-4-yl-3-pyridin-4-ylpyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	362269: Inhibition of ERK1/2 phosphorylation in human MALME3M cells	ic50	0.0090	uM
13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0090	uM
7-[(3,4-difluorophenyl)methyl]-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0091	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	701075: Inhibition of ERK1/2 in OVA-challenged and IgE-sensitized cells	ec50	0.0100	uM
(NE)-N-[5-[1-(1-methylpiperidin-4-yl)-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	362269: Inhibition of ERK1/2 phosphorylation in human MALME3M cells	ic50	0.0100	uM
6-benzyl-3-pyridin-4-yl-5,8-dihydro-1H-pyrazolo[4,5-g]quinazolin-7-one	1896225: Inhibition of ERK1 (unknown origin)	ic50	0.0100	uM
(1S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]-5-fluorospiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0100	uM
2-[(3-chlorophenyl)methyl]-7-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1-one	1527684: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of RSK phosphorylation after 2 hrs	ic50	0.0100	uM
(4R,7S,8S)-13-(8-ethynylnaphthalen-1-yl)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene	2011753: Inhibition of ERK1/2 phosphorylation in human PANC-1 cells incubated for 3 hrs	ic50	0.0100	uM
N-[2-[[2-[(2-methoxy-5-methyl-4-pyridinyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide	1896225: Inhibition of ERK1 (unknown origin)	ic50	0.0100	uM
(3R)-3-methyl-7-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-2-[(6-methyl-2-pyridinyl)methyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1-one	1527683: Inhibition of ERK1/2 in human A375 cells assessed as inhibition of ERK phosphorylation after 2 hrs	ic50	0.0120	uM
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]pyridin-2-one	1625969: Inhibition of ERK1 (unknown origin)	ic50	0.0130	uM
2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-(3-methylanilino)pyrimidine-5-carboxamide	622870: Inhibition of Erk1/2 phosphorylation expressed in ramos cells after 30 mins by MSD assay	ic50	0.0158	uM
3-(2-methyl-4-pyridinyl)-N-[(2,3,5-trichloro-4-pyridinyl)methyl]-1H-indazole-5-carboxamide	1298207: Inhibition of human recombinant GST-tagged ERK1 expressed in Escherichia coli using ser/thr 3 Peptide as substrate preincubated for 1 hr measured after 1 hr by Z-LYTE assay	ic50	0.0167	uM
(3S)-1-[2-[4-[4-[5-(ethylamino)-1,3,4-oxadiazol-2-yl]phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-N-[3-(4-fluorophenyl)-1H-indazol-5-yl]-3-methylsulfanylpyrrolidine-3-carboxamide	1385274: Inhibition of ERK1 (unknown origin) using peptide substrate measured after 45 mins by IMAP assay	ic50	0.0170	uM
(5S)-1’-[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl]-2-methylspiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2039007: Inhibition of ERK1/2 phosphorylation at Thr202/Tyr204 residues in human KYSE520 cells incubated for 1 hrs by Western blot analysis	ic50	0.0170	uM

CTD chemical–gene interactions

1266 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases response to substance, increases localization, affects cotreatment, decreases reaction, increases reaction (+10 more)	180
U 0126	increases phosphorylation, increases activity, decreases phosphorylation, decreases activity, decreases response to substance (+10 more)	157
Tetradecanoylphorbol Acetate	increases reaction, decreases activity, affects localization, increases localization, increases phosphorylation (+5 more)	68
Acetylcysteine	increases phosphorylation, affects reaction, decreases expression, affects cotreatment, decreases reaction (+4 more)	63
Resveratrol	decreases reaction, increases phosphorylation, increases localization, increases reaction, affects binding (+9 more)	60
Arsenic Trioxide	affects binding, decreases expression, decreases reaction, decreases phosphorylation, increases reaction (+6 more)	52
sodium arsenite	decreases activity, increases activity, increases phosphorylation, increases reaction, affects reaction (+7 more)	51
Cadmium Chloride	increases abundance, affects cotreatment, decreases response to substance, affects reaction, decreases expression (+7 more)	47
bisphenol A	affects cotreatment, decreases activity, increases activity, increases expression, affects reaction (+7 more)	42
Estradiol	affects cotreatment, decreases reaction, increases activity, increases reaction, affects reaction (+7 more)	41
RTKI cpd	increases phosphorylation, affects cotreatment, increases activity, decreases activity, decreases reaction (+3 more)	39
Quercetin	decreases expression, decreases activity, decreases reaction, increases expression, decreases phosphorylation (+4 more)	39
Cadmium	increases reaction, affects phosphorylation, affects uptake, decreases reaction, affects reaction (+5 more)	34
Hydrogen Peroxide	decreases reaction, increases activity, increases phosphorylation, increases oxidation, decreases phosphorylation (+5 more)	29
Particulate Matter	affects reaction, increases activity, increases abundance, increases reaction, decreases phosphorylation (+6 more)	29
Sorafenib	increases phosphorylation, decreases phosphorylation, affects phosphorylation, decreases reaction, increases activity (+4 more)	26
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, decreases expression, decreases activity, decreases phosphorylation, decreases reaction (+3 more)	24
Lipopolysaccharides	increases activity, increases phosphorylation, increases reaction, decreases reaction, affects reaction (+1 more)	24
Gefitinib	affects reaction, increases phosphorylation, increases activity, affects cotreatment, increases expression (+6 more)	22
Fulvestrant	increases activity, decreases response to substance, decreases reaction, increases expression, increases phosphorylation (+2 more)	21
Cisplatin	affects activity, decreases phosphorylation, decreases response to substance, increases response to substance, increases activity (+6 more)	19
Doxorubicin	increases phosphorylation, affects activity, affects phosphorylation, decreases expression, decreases phosphorylation (+8 more)	18
Tretinoin	decreases reaction, increases activity, increases reaction, affects phosphorylation, decreases phosphorylation (+7 more)	18
Plant Extracts	affects phosphorylation, decreases expression, increases reaction, increases phosphorylation, affects localization (+5 more)	17
Benzo(a)pyrene	increases methylation, affects reaction, increases expression, decreases reaction, increases reaction (+7 more)	16
Wortmannin	affects cotreatment, decreases reaction, increases phosphorylation, increases reaction, increases activity (+2 more)	15
Curcumin	decreases reaction, increases activity, increases reaction, decreases phosphorylation, decreases activity (+5 more)	15
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	decreases reaction, increases phosphorylation, affects binding, increases activity, decreases activity (+2 more)	14
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	increases reaction, increases abundance, increases expression, decreases phosphorylation, decreases reaction (+2 more)	14
Nicotine	affects cotreatment, decreases phosphorylation, increases activity, decreases response to substance, decreases reaction (+5 more)	14

ChEMBL screening assays

964 unique, capped per target: 950 binding, 9 functional, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008211	Binding	Inhibition of ERK1/2 phosphorylation in human MALME3M cells	Potent and selective pyrazole-based inhibitors of B-Raf kinase. — Bioorg Med Chem Lett
CHEMBL4423934	ADMET	Effect on ERK1/2 phosphorylation at T202/Y204 residues in mouse RAW264.7 cells at 5 uM measured after 30 mins by Western blot analysis	Physalactone and 4β-Hydroxywithanolide E Isolated from Physalis peruviana Inhibit LPS-Induced Expression of COX-2 and iNOS Accompanied by Abatement of Akt and STAT1. — J Nat Prod
CHEMBL709032	Functional	Inhibit ion of MAPK phosphorylation in LoVo cells	Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. — Bioorg Med Chem Lett

Cellosaurus cell lines

22 cell lines: 21 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0028	AN3-CA	Cancer cell line	Female
CVCL_0445	MeWo	Cancer cell line	Male
CVCL_1122	CHL-1	Cancer cell line	Female
CVCL_1992	COLO 699	Cancer cell line	Female
CVCL_1993	COLO 699N	Cancer cell line	Female
CVCL_AZ60	MeWo CIS 0.01	Cancer cell line	Male
CVCL_AZ61	MeWo ETO 0.1	Cancer cell line	Male
CVCL_AZ62	MeWo ETO 1	Cancer cell line	Male
CVCL_AZ63	MeWo VIN 0.5	Cancer cell line	Male
CVCL_AZ74	MeWo CIS 1	Cancer cell line	Male

Clinical trials (associated diseases)

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