MAP2K1

Summary

MAP2K1 (mitogen-activated protein kinase kinase 1, HGNC:6840) is a protein-coding gene on chromosome 15q22.31, encoding Dual specificity mitogen-activated protein kinase kinase 1 (Q02750). Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. In precision oncology, MAP2K1 Q56_V60del confers sensitivity to Selumetinib in Ovarian Serous Carcinoma (CIViC Level C); 7 further curated variant–drug associations are listed below.

The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development.

Source: NCBI Gene 5604 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiofaciocutaneous syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 727 total — 25 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 155
• Druggable target: yes — 54 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 8 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 5 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002755

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6840
Approved symbol	MAP2K1
Name	mitogen-activated protein kinase kinase 1
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	MEK1, MAPKK1, MKK1
Ensembl gene	ENSG00000169032
Ensembl biotype	protein_coding
OMIM	176872
Entrez	5604

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000307102, ENST00000425818, ENST00000566326, ENST00000684779, ENST00000685172, ENST00000685763, ENST00000686347, ENST00000687191, ENST00000687481, ENST00000688689, ENST00000689951, ENST00000691077, ENST00000691576, ENST00000691937, ENST00000692487, ENST00000692683, ENST00000693150, ENST00000901531, ENST00000901532, ENST00000901533, ENST00000901534, ENST00000920479, ENST00000920480

RefSeq mRNA: 2 — MANE Select: NM_002755 NM_001411065, NM_002755

CCDS: CCDS10216, CCDS92029

Canonical transcript exons

ENST00000307102 — 11 exons

Exon	Start	End
ENSE00001134055	66444656	66444707
ENSE00001199370	66489718	66489763
ENSE00001199374	66489215	66489276
ENSE00001199379	66487228	66487292
ENSE00001199390	66481755	66481879
ENSE00001257056	66484990	66485191
ENSE00001257104	66386912	66387427
ENSE00002629369	66490502	66491544
ENSE00003549291	66443280	66443357
ENSE00003568990	66436746	66436892
ENSE00003630653	66435027	66435237

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.1889 / max 862.7390, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147265	25.6283	1817
147266	21.9570	1815
147270	0.3224	99
147269	0.1437	63
147267	0.1374	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.73	gold quality
oocyte	CL:0000023	99.42	gold quality
orbitofrontal cortex	UBERON:0004167	97.99	gold quality
prefrontal cortex	UBERON:0000451	97.73	gold quality
postcentral gyrus	UBERON:0002581	96.87	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.78	gold quality
parietal lobe	UBERON:0001872	96.74	gold quality
superior frontal gyrus	UBERON:0002661	96.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.44	gold quality
frontal cortex	UBERON:0001870	96.39	gold quality
nucleus accumbens	UBERON:0001882	96.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.29	gold quality
cingulate cortex	UBERON:0003027	96.06	gold quality
anterior cingulate cortex	UBERON:0009835	96.00	gold quality
neocortex	UBERON:0001950	95.99	gold quality
monocyte	CL:0000576	95.96	gold quality
mononuclear cell	CL:0000842	95.90	gold quality
leukocyte	CL:0000738	95.87	gold quality
Ammon’s horn	UBERON:0001954	95.84	gold quality
cerebral cortex	UBERON:0000956	95.80	gold quality
pons	UBERON:0000988	95.80	gold quality
esophagus squamous epithelium	UBERON:0006920	95.77	gold quality
epithelium of esophagus	UBERON:0001976	95.75	gold quality
frontal pole	UBERON:0002795	95.63	gold quality
telencephalon	UBERON:0001893	95.52	gold quality
gastrocnemius	UBERON:0001388	95.49	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.44	gold quality
middle temporal gyrus	UBERON:0002771	95.30	gold quality
lower esophagus mucosa	UBERON:0035834	95.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	36.62
E-ANND-3	yes	20.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CEBPA	Activation
ENO1	Activation
FOS	Activation
PLVAP	Activation

Upstream regulators (CollecTRI, top): AP1, ATF3, CEBPB, FOS, IRF3, IRF6, JUN, JUNB, MXD1, MYC, NFATC1, NFKB, NFKBIA, NR1I2, NR4A1, PAX1, SMAD7, SP1, SP3, TP53, ZHX2

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

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)
• MEK1 interacts with and phosphorylates ERK2. This interaction is mediated via a conserved N-terminal docking site in MEK1. Note that this interaction was demonstrated using rat ERK2. (PMID:11134045)
• Laminin-10/11 and fibronectin differentially prevent apoptosis induced by serum removal via phosphatidylinositol 3-kinase/Akt- and MEK1/ERK-dependent pathways (Laminin 10; separate entry for Laminin 11). (PMID:11891225)
• PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway (PMID:11948406)
• MEK1 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 MEK1 activity and dual-phosphorylation. (PMID:12032872)
• Activation of a Src-dependent Raf-MEK1/2-ERK signaling pathway is required for IL-1alpha-induced upregulation of beta-defensin 2 in human middle ear epithelial cells. (PMID:12063167)
• MEK1 has an activation domain that forms a hydrophobic binding pocket for enzyme inhibitor PD184352 (PMID:12370306)
• Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways (PMID:12456688)
• the NH(2)-terminal end of MEK is important not only for substrate interaction but also for catalytic activity (PMID:12522135)
• 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)
• the dramatic activation of an endomembrane-associated MEK1 without the corresponding activation of the MEK substrate ERK during normal G(2)/M (PMID:12609978)
• Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I-induced increase in VEGF secretion and promoter activity (PMID:12612059)
• serum stimulation of fibroblasts in floating matrices does not result in ERK translocation to the nucleus. In addition, there was decreased serum activation of upstream members of the ERK signaling pathway, MEK and Raf (PMID:12663662)
• 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)
• Inhibition of the upstream MAPK kinase inhibited the phosphorylation of ERK; modulated the levels of Bcl-2, Mcl-1, and cFLIP; and induced G2M cell-cycle arrest or apoptosis (PMID:12689928)
• Distribution of total MEK1 between Alzheimer disease[AD] and age-matched control cases was similar but increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (PMID:12807433)
• results show that p38-mediated dephosphorylation of MEK1,2 mediates initiation of apoptosis (PMID:12839928)
• constituitively activated in choroidal melanoma cell lines, independent of Ras, and regulated by B-RafV599E (PMID:12917419)
• RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. (PMID:14581471)
• MEK1,2 response element that mediates angiotensin II-stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation. (PMID:14656894)
• Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38mapk and MEK1/2 similarly increase cytolysis resulting from O2-. (PMID:14672918)
• Glycogen synthase kinase-3beta is tyrosine-phosphorylated by mitogen-activated protein kinase kinase 1 in fibroblasts. (PMID:15020233)
• Plk3 may be a key protein kinase mediating MEK1 function in the Golgi fragmentation pathway during cell division. (PMID:15021912)
• in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFkappaB-independent, IL-8 and MIP3alpha expression. (PMID:15069060)
• Has distinct ways to contribute to a regulated ERK activity and cell cycle progression. (PMID:15284233)
• Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress. (PMID:15292274)
• Detailed pathway analysis revealed that BM stromal cells stimulate STAT3 via the IL-6R, and MEK1/ERK1 pathways, via IL-6R-independent mechanisms (PMID:15297310)
• Arsenic trioxide and inhibitors of this enzyme my be combined as anticancer agents for acute promyelocytic leukemia. (PMID:15538402)
• X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively (PMID:15543157)
• Integrin alphav controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling. (PMID:15557124)
• MEK1 facilitates ligand-initiated transcriptional activation while targeting the Ah receptor for degradation (PMID:15572374)
• Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA. (PMID:15615716)
• Selesctive inhibitors potentiate apoptosis induction by sulindac sulfide, an NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer. (PMID:15657353)
• The induction of the raf-1/MEK1 pathway blocks IGF-1-mediated intracellular neuroendocrine hormone regulation. This pathway may be a therapeutic target in gastrointestinal carcinoid tumor therapy. (PMID:15657590)
• whereas MAPKK-1 signaling is required for VEGF synthesis only and PI3K activation activity was lowered in hypoxia. (PMID:15665520)
• RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 (PMID:15757891)
• Cdc2 inhibits growth factor receptor-mediated ERK activation during mitosis by primarily targeting signaling proteins that are upstream of MEK1 (PMID:15888452)
• The ability of constitutively-active human MEK1 to stimulate ERK phosphorylation and to induce the neoplastic transformation of NIH 3T3 cells required the integrity of the D-site was found. (PMID:15979847)
• results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop (PMID:16086581)
• PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1 (PMID:16239230)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	map2k1	ENSDARG00000007825
mus_musculus	Map2k1	ENSMUSG00000004936
rattus_norvegicus	Map2k1	ENSRNOG00000010176
drosophila_melanogaster	Dsor1	FBGN0010269
caenorhabditis_elegans	mek-2	WBGENE00003186

Paralogs (8): MAP2K4 (ENSG00000065559), MAP2K7 (ENSG00000076984), MAP3K4 (ENSG00000085511), MAP2K2 (ENSG00000126934), NEK1 (ENSG00000137601), MAP2K5 (ENSG00000137764), MAP3K2 (ENSG00000169967), MAP3K3 (ENSG00000198909)

Protein

Protein identifiers

Dual specificity mitogen-activated protein kinase kinase 1 — Q02750 (reviewed: Q02750)

Alternative names: ERK activator kinase 1, MAPK/ERK kinase 1

All UniProt accessions (13): A0A8I5KRX5, A0A8I5KVF6, A0A8I5KXN4, A0A8I5KYB4, A0A8I5KYS7, A0A8I5QJ96, A0A8I5QJC1, A0A8I5QJL9, A0A8I5QJP8, A4QPA9, B4DFY5, Q02750, H3BRW9

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of 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.

Subunit / interactions. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Forms a heterodimer with MAP2K2/MEK2. Forms heterodimers with KSR2 which further dimerize to form tetramers. Interacts with KSR1 or KSR2 and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or KSR2-BRAF dimerization. Interacts with ARBB2, LAMTOR3 and RAF1. Interacts with MAPK1/ERK2. Interacts with MORG1. Interacts with PPARG. Interacts with isoform 1 of VRK2. Interacts with SGK1. Interacts with BIRC6/bruce. Interacts with KAT7; the interaction promotes KAT7 phosphorylation. Interacts with RAF1 and NEK10; the interaction is required for ERK1/2-signaling pathway activation in response to UV irradiation. Interacts with TRAF3IP3. Interacts with MOS. (Microbial infection) Interacts with Yersinia YopJ.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle pole body. Nucleus. Membrane.

Tissue specificity. Widely expressed, with extremely low levels in brain.

Post-translational modifications. Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK. Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation. (Microbial infection) Acetylation by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.

Disease relevance. Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279] A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. The disease is caused by variants affecting the gene represented in this entry. Melorheostosis, isolated (MEL) [MIM:155950] A sclerosing bone disorder characterized by hyperostosis of the cortex of tubular bones, frequently involving one limb. The lesions may be accompanied by abnormalities of adjacent soft tissue, joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangioma. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains. This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A. Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766.

Domain organisation. The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q02750-1	1, MKK1a	yes
Q02750-2	2, MKK1b

RefSeq proteins (2): NP_001397994, NP_002746* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050915	MAP_kinase_kinase	Family

Pfam: PF00069

Enzyme classification (BRENDA):

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

Substrate kinetics (BRENDA)

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

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

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• 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 (74 total): helix 19, mutagenesis site 13, binding site 10, strand 7, sequence variant 6, modified residue 5, turn 5, region of interest 2, sequence conflict 2, chain 1, domain 1, site 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

94 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7B7R	X-RAY DIFFRACTION	1.7
7B9L	X-RAY DIFFRACTION	1.7
3EQC	X-RAY DIFFRACTION	1.8
3EQI	X-RAY DIFFRACTION	1.9
3EQH	X-RAY DIFFRACTION	2
3VVH	X-RAY DIFFRACTION	2
7B94	X-RAY DIFFRACTION	2
7F2X	X-RAY DIFFRACTION	2.01
9AXX	X-RAY DIFFRACTION	2.07
3EQD	X-RAY DIFFRACTION	2.1
4AN3	X-RAY DIFFRACTION	2.1
7XLP	X-RAY DIFFRACTION	2.1
7XNC	X-RAY DIFFRACTION	2.1
3ZLY	X-RAY DIFFRACTION	2.11
3ZLW	X-RAY DIFFRACTION	2.12
7PQV	X-RAY DIFFRACTION	2.13
3W8Q	X-RAY DIFFRACTION	2.2
3ZLX	X-RAY DIFFRACTION	2.2
4ANB	X-RAY DIFFRACTION	2.2
3DV3	X-RAY DIFFRACTION	2.3
3SLS	X-RAY DIFFRACTION	2.3
7B3M	X-RAY DIFFRACTION	2.3
8YP4	X-RAY DIFFRACTION	2.35
3ZM4	X-RAY DIFFRACTION	2.37
1S9J	X-RAY DIFFRACTION	2.4
5HZE	X-RAY DIFFRACTION	2.4
6X2P	X-RAY DIFFRACTION	2.4
9AY7	X-RAY DIFFRACTION	2.41
9AXM	X-RAY DIFFRACTION	2.42
6X2X	X-RAY DIFFRACTION	2.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02750-F1	84.05	0.63

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 (2): 8–9 (cleavage; by anthrax lethal factor); 190 (proton acceptor)

Ligand- & substrate-binding residues (10): 150–153; 192–195; 194; 208–211; 208; 74–82; 97; 97; 143–146; 144–146

Post-translational modifications (5): 218, 222, 286, 292, 298

Mutagenesis-validated functional residues (13):

Position	Phenotype
97	loss of catalytic activity. strongly reduces phosphorylation upon uv irradiation.
97	loss of catalytic activity. no effect on braf-ksr1 or braf-ksr2 dimerization.
150	no loss of activity.
212	no loss of activity.
218	loss of catalytic activity. no effect on braf-ksr1 dimerization; when associated with a-222.
218	no effect on braf-ksr1 dimerization; when associated with d-222.
219	increases interaction with ksr1 and braf.
219	increases interaction with ksr1 and braf; when associated with l-220.
220	increases interaction with ksr1 and braf; when associated with w-219.
221	increases interaction with ksr1 and braf.
222	loss of catalytic activity. no effect on braf-ksr1 dimerization; when associated with a-218.
222	no effect on braf-ksr1 dimerization; when associated with d-218.
311	loss of interaction with braf and ksr1. loss of braf-ksr1 dimerization.

Function

Pathways and Gene Ontology

Reactome pathways

61 pathways

ID	Pathway
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-170968	Frs2-mediated activation
R-HSA-445144	Signal transduction by L1
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-5673000	RAF activation
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-5674499	Negative feedback regulation of MAPK pathway
R-HSA-5684264	MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9652169	Signaling by MAP2K mutants
R-HSA-9656223	Signaling by RAF1 mutants
R-HSA-112409	RAF-independent MAPK1/3 activation
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade

MSigDB gene sets: 1152 (showing top): PID_BCR_5PATHWAY, PID_SHP2_PATHWAY, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_REGULATION_OF_GOLGI_ORGANIZATION, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, BIOCARTA_FMLP_PATHWAY, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT

GO Biological Process (59): MAPK cascade (GO:0000165), regulation of vascular associated smooth muscle contraction (GO:0003056), chemotaxis (GO:0006935), response to oxidative stress (GO:0006979), signal transduction (GO:0007165), heart development (GO:0007507), negative regulation of cell population proliferation (GO:0008285), positive regulation of autophagy (GO:0010508), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), Schwann cell development (GO:0014044), cerebellar cortex formation (GO:0021697), central nervous system neuron differentiation (GO:0021953), neuron differentiation (GO:0030182), keratinocyte differentiation (GO:0030216), positive regulation of cell migration (GO:0030335), thyroid gland development (GO:0030878), melanosome transport (GO:0032402), regulation of stress-activated MAPK cascade (GO:0032872), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), negative regulation of homotypic cell-cell adhesion (GO:0034111), endodermal cell differentiation (GO:0035987), ERBB2-ERBB3 signaling pathway (GO:0038133), myelination (GO:0042552), type B pancreatic cell proliferation (GO:0044342), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of muscle contraction (GO:0045933), positive regulation of Ras protein signal transduction (GO:0046579), vesicle transport along microtubule (GO:0047496), insulin-like growth factor receptor signaling pathway (GO:0048009), Golgi inheritance (GO:0048313), thymus development (GO:0048538), response to axon injury (GO:0048678), regulation of axon regeneration (GO:0048679), neuron projection morphogenesis (GO:0048812), cell motility (GO:0048870), positive regulation of axonogenesis (GO:0050772), response to glucocorticoid (GO:0051384), Bergmann glial cell differentiation (GO:0060020), face development (GO:0060324)

GO Molecular Function (19): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), protein serine/threonine/tyrosine kinase activity (GO:0004712), protein tyrosine kinase activity (GO:0004713), MAP kinase scaffold activity (GO:0005078), ATP binding (GO:0005524), protein kinase activator activity (GO:0030295), small GTPase binding (GO:0031267), mitogen-activated protein kinase kinase kinase binding (GO:0031435), protein serine/threonine kinase activator activity (GO:0043539), protein-containing complex binding (GO:0044877), scaffold protein binding (GO:0097110), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), protein kinase binding (GO:0019901)

GO Cellular Component (25): nucleus (GO:0005634), mitochondrion (GO:0005739), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), postsynaptic density (GO:0014069), axon (GO:0030424), dendrite cytoplasm (GO:0032839), ciliary basal body (GO:0036064), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020), dendrite (GO:0030425), vesicle (GO:0031982), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Oncogenic MAPK signaling	6
RAF/MAP kinase cascade	2
RAF-independent MAPK1/3 activation	1
Prolonged ERK activation events	1
L1CAM interactions	1
Uptake and actions of bacterial toxins	1
Negative regulation of MAPK pathway	1
MAP kinase activation	1
Interleukin-1 signaling	1
Signaling by RAS mutants	1
MAPK1/MAPK3 signaling	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	6
protein kinase activity	5
intracellular membrane-bounded organelle	4
cellular anatomical structure	4
gene expression	2
regulation of gene expression	2
MAPK cascade	2
binding	2
endosome	2
endomembrane system	2
microtubule organizing center	2
cell periphery	2
intracellular signaling cassette	1
regulation of smooth muscle contraction	1
vascular associated smooth muscle contraction	1
regulation of vasoconstriction	1
response to chemical	1
taxis	1
response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
Schwann cell differentiation	1
glial cell development	1
cerebellar cortex morphogenesis	1
anatomical structure formation involved in morphogenesis	1
central nervous system development	1
neuron differentiation	1

Protein interactions and networks

STRING

5242 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K1	BRAF	P15056	983
MAP2K1	MAPK3	P27361	975
MAP2K1	LAMTOR3	Q9UHA4	974
MAP2K1	RAF1	P04049	970
MAP2K1	IQGAP1	P46940	962
MAP2K1	TRIB1	Q96RU8	951
MAP2K1	MAPK1	P28482	950
MAP2K1	KSR1	Q8IVT5	941
MAP2K1	ARRB2	P32121	934
MAP2K1	KRAS	P01116	883
MAP2K1	HRAS	P01112	833
MAP2K1	PTPN11	Q06124	832
MAP2K1	GRK2	P25098	825
MAP2K1	PIK3CA	P42336	815
MAP2K1	NRAS	P01111	814

IntAct

255 interactions, top by confidence:

A	B	Type	Score
MAP2K1	BRAF	psi-mi:“MI:0915”(physical association)	0.980
MAP2K1	BRAF	psi-mi:“MI:0407”(direct interaction)	0.980
BRAF	MAP2K1	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
MAP2K1	BRAF	psi-mi:“MI:0914”(association)	0.980
BRAF	MAP2K1	psi-mi:“MI:0915”(physical association)	0.980
MAP2K1	BRAF	psi-mi:“MI:2364”(proximity)	0.980
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
RAF1	MAP2K1	psi-mi:“MI:0915”(physical association)	0.960
RAF1	MAP2K1	psi-mi:“MI:0914”(association)	0.960
MAP2K1	RAF1	psi-mi:“MI:0407”(direct interaction)	0.960
MAP2K1	RAF1	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (447): MAP2K1 (Affinity Capture-Western), MAP2K1 (Affinity Capture-Western), MAP2K1 (Affinity Capture-Western), MAP2K1 (Affinity Capture-Western), BANP (Two-hybrid), MAP2K1 (Affinity Capture-Western), MAP2K1 (Co-fractionation), MAP2K1 (Affinity Capture-Western), PPARG (Affinity Capture-Western), MAP2K1 (Reconstituted Complex), MAP2K1 (Affinity Capture-Western), MAP2K1 (Biochemical Activity), MAP2K1 (Affinity Capture-MS), MAP2K1 (Affinity Capture-MS), MAP2K1 (Co-fractionation)

ESM2 similar proteins: A0A1S4CGX4, A9RWC9, A9S5R3, A9SR33, O01775, O14047, O14733, O44408, O80396, P10506, P18652, P18654, P29678, P31938, P36506, P36507, P51812, Q01986, Q02750, Q03428, Q05116, Q08942, Q10664, Q13163, Q18846, Q1HG70, Q20347, Q21307, Q24324, Q4KSH7, Q4V3C8, Q5QN75, Q62862, Q63932, Q63980, Q7TPS0, Q8MXI4, Q91447, Q94A06, Q99JT2

Diamond homologs: A0A194VNL2, A0A1S4CGX4, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, A9RWC9, A9S5R3, A9SR33, B0XPE4, C4YLK8, E1BK52, F1NBT0, G4N6Z6, G4NEB8, G5EDF7, O00506, O09110, O14733, O54748, O80396, O94804, O95819, P06784, P08018, P0CY25, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

74 interactions.

A	Effect	B	Mechanism
U0126	down-regulates	MAP2K1	“chemical inhibition”
MAP3K2	up-regulates	MAP2K1	phosphorylation
MAP2K1	down-regulates	TAL1	phosphorylation
WDR83	up-regulates	MAP2K1	binding
MAP3K8	up-regulates	MAP2K1	phosphorylation
LAMTOR3	up-regulates	MAP2K1	binding
PAK	up-regulates	MAP2K1	phosphorylation
PPP2CA	down-regulates	MAP2K1	dephosphorylation
MAP2K1	down-regulates	MAPK14
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide	down-regulates	MAP2K1	“chemical inhibition”
selumetinib	down-regulates	MAP2K1	“chemical inhibition”
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	down-regulates	MAP2K1	“chemical inhibition”
trametinib	down-regulates	MAP2K1	“chemical inhibition”
PD318088	down-regulates	MAP2K1	“chemical inhibition”
2-(2-amino-3-methoxyphenyl)chromen-4-one	down-regulates	MAP2K1	“chemical inhibition”
U0126.EtOH	down-regulates	MAP2K1	“chemical inhibition”
MAP2K1	up-regulates	MAPK3	phosphorylation
FGFR1	up-regulates	MAP2K1
MAP2K1	“up-regulates activity”	MAPK1	phosphorylation
ARAF	up-regulates	MAP2K1	phosphorylation
RAF1	“up-regulates activity”	MAP2K1	phosphorylation
PAK1	“up-regulates activity”	MAP2K1	phosphorylation
MAPK1	“down-regulates activity”	MAP2K1	phosphorylation
MAP2K1	down-regulates	IRS1	phosphorylation
MAP2K1	“up-regulates activity”	GSK3B	phosphorylation
PDPK1	“up-regulates activity”	MAP2K1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	39.7×	2e-07
Signaling by high-kinase activity BRAF mutants	13	35.9×	8e-15
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	35.0×	4e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	35.0×	4e-07
MAP2K and MAPK activation	13	32.3×	2e-14
Signaling by RAF1 mutants	13	31.5×	2e-14
Signaling by RAS mutants	8	29.4×	1e-08
Insulin receptor signalling cascade	5	29.2×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
Schwann cell development	6	46.1×	1e-06
face development	5	29.3×	1e-04
thyroid gland development	5	19.8×	6e-04
MAPK cascade	16	17.9×	8e-13
ERK1 and ERK2 cascade	7	16.2×	7e-05
protein targeting	5	13.4×	3e-03
myelination	7	12.8×	2e-04
thymus development	5	12.3×	4e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

MAP2K1 is a dual-specificity kinase known for it’s involvement in the ERK pathway by activation of ERK1 and ERK2. MAP2K1 activating mutations have been observed in a number of cancers including ovarian, melanoma and lung. These activating mutations are generally found in the N-terminal negative regulatory region or the ATP-binding region of the N-terminal lobe. Inhibitors of MEK genes have been shown to inhibit tumor growth in these cases.

From intOGen — cancer-driver classification: activating (oncogene-like) across 5 cancer types — DLBCLNOS, LUAD, MEL, NSCLC, SKCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	26
Uncertain significance	295
Likely benign	267
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1297058	NM_002755.4(MAP2K1):c.383G>C (p.Gly128Ala)	Pathogenic
1328146	NM_002755.4(MAP2K1):c.607G>C (p.Glu203Gln)	Pathogenic
13351	NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)	Pathogenic
1506502	NM_002755.4(MAP2K1):c.161T>C (p.Leu54Pro)	Pathogenic
167260	NM_002755.4(MAP2K1):c.608A>G (p.Glu203Gly)	Pathogenic
1691385	NM_002755.4(MAP2K1):c.303_308del (p.Glu102_Ile103del)	Pathogenic
1708637	NM_002755.4(MAP2K1):c.170A>T (p.Lys57Met)	Pathogenic
190378	NM_002755.4(MAP2K1):c.305A>G (p.Glu102Gly)	Pathogenic
228273	NM_002755.4(MAP2K1):c.364A>G (p.Asn122Asp)	Pathogenic
3375745	NM_002755.4(MAP2K1):c.608A>T (p.Glu203Val)	Pathogenic
372636	NM_002755.4(MAP2K1):c.371C>G (p.Pro124Arg)	Pathogenic
375978	NM_002755.4(MAP2K1):c.167A>C (p.Gln56Pro)	Pathogenic
375981	NM_002755.4(MAP2K1):c.370C>T (p.Pro124Ser)	Pathogenic
376173	NM_002755.4(MAP2K1):c.169A>G (p.Lys57Glu)	Pathogenic
376194	NM_002755.4(MAP2K1):c.332T>A (p.Ile111Asn)	Pathogenic
3774512	NM_002755.4(MAP2K1):c.171_185del (p.Gln58_Glu62del)	Pathogenic
3774514	NM_002755.4(MAP2K1):c.171G>C (p.Lys57Asn)	Pathogenic
40741	NM_002755.4(MAP2K1):c.355C>T (p.His119Tyr)	Pathogenic
40743	NM_002755.4(MAP2K1):c.371C>A (p.Pro124Gln)	Pathogenic
40745	NM_002755.4(MAP2K1):c.383_384delinsTT (p.Gly128Val)	Pathogenic
40781	NM_002755.4(MAP2K1):c.199G>A (p.Asp67Asn)	Pathogenic
44587	NM_002755.4(MAP2K1):c.124C>T (p.Leu42Phe)	Pathogenic
44588	NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)	Pathogenic
636238	NM_002755.4(MAP2K1):c.388T>A (p.Tyr130Asn)	Pathogenic
981554	NM_002755.4(MAP2K1):c.608A>C (p.Glu203Ala)	Pathogenic
1299563	NM_002755.4(MAP2K1):c.265C>A (p.Pro89Thr)	Likely pathogenic
13350	NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)	Likely pathogenic
1697313	NM_002755.4(MAP2K1):c.370C>G (p.Pro124Ala)	Likely pathogenic
1723651	NM_002755.4(MAP2K1):c.125T>G (p.Leu42Arg)	Likely pathogenic
1878870	NM_002755.4(MAP2K1):c.730T>A (p.Ser244Thr)	Likely pathogenic

SpliceAI

1916 predictions. Top by Δscore:

Variant	Effect	Δscore
15:66387423:GCGGA:G	donor_gain	1.0000
15:66387424:CGGA:C	donor_gain	1.0000
15:66387425:GGA:G	donor_gain	1.0000
15:66387425:GGAG:G	donor_gain	1.0000
15:66387426:GA:G	donor_gain	1.0000
15:66387426:GAG:G	donor_gain	1.0000
15:66387427:AGTA:A	donor_loss	1.0000
15:66387428:G:GG	donor_gain	1.0000
15:66387428:GTAA:G	donor_loss	1.0000
15:66387429:T:G	donor_loss	1.0000
15:66435015:A:AG	acceptor_gain	1.0000
15:66435015:ACTTT:A	acceptor_gain	1.0000
15:66435016:C:G	acceptor_gain	1.0000
15:66435019:T:TA	acceptor_gain	1.0000
15:66435020:G:A	acceptor_gain	1.0000
15:66435025:A:AG	acceptor_gain	1.0000
15:66435025:A:T	acceptor_loss	1.0000
15:66435025:AG:A	acceptor_gain	1.0000
15:66435026:G:GA	acceptor_gain	1.0000
15:66435026:GG:G	acceptor_gain	1.0000
15:66435026:GGA:G	acceptor_gain	1.0000
15:66435026:GGACC:G	acceptor_gain	1.0000
15:66435233:GAAAG:G	donor_gain	1.0000
15:66435234:AAAG:A	donor_loss	1.0000
15:66435235:AAGG:A	donor_loss	1.0000
15:66435235:AAGGT:A	donor_gain	1.0000
15:66435238:G:GG	donor_gain	1.0000
15:66436734:A:AG	acceptor_gain	1.0000
15:66436735:C:G	acceptor_gain	1.0000
15:66436741:TCCA:T	acceptor_loss	1.0000

AlphaMissense

2598 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:66435095:T:C	L50P	1.000
15:66435103:T:C	F53L	1.000
15:66435104:T:C	F53S	1.000
15:66435105:T:A	F53L	1.000
15:66435105:T:G	F53L	1.000
15:66435107:T:C	L54P	1.000
15:66435167:T:C	L74P	1.000
15:66435169:G:A	G75R	1.000
15:66435169:G:C	G75R	1.000
15:66435169:G:T	G75W	1.000
15:66435170:G:A	G75E	1.000
15:66435170:G:T	G75V	1.000
15:66435175:G:A	G77S	1.000
15:66435175:G:C	G77R	1.000
15:66435175:G:T	G77C	1.000
15:66435176:G:A	G77D	1.000
15:66435176:G:C	G77A	1.000
15:66435176:G:T	G77V	1.000
15:66435181:G:C	G79R	1.000
15:66435182:G:A	G79D	1.000
15:66435184:G:C	G80R	1.000
15:66435185:G:A	G80D	1.000
15:66435185:G:T	G80V	1.000
15:66435190:G:A	V82M	1.000
15:66435191:T:A	V82E	1.000
15:66435230:C:A	A95D	1.000
15:66435235:A:C	K97Q	1.000
15:66435235:A:G	K97E	1.000
15:66435236:A:T	K97M	1.000
15:66435237:G:C	K97N	1.000

dbSNP variants (sampled 300 via entrez): RS1000027199 (15:66487882 G>A), RS1000028009 (15:66410687 C>T), RS1000063731 (15:66398875 G>T), RS1000090708 (15:66479069 G>A), RS1000144547 (15:66478795 T>C), RS1000230952 (15:66454324 G>A,C), RS1000232146 (15:66399399 G>A), RS1000248924 (15:66416646 C>T), RS1000283255 (15:66454144 A>T), RS1000395083 (15:66460532 T>C), RS1000437923 (15:66423276 A>G), RS1000439610 (15:66471833 C>A,T), RS1000479109 (15:66452492 T>A), RS1000492478 (15:66410932 C>T), RS1000519140 (15:66405918 C>T)

Disease associations

OMIM: gene MIM:176872 | disease phenotypes: MIM:615279, MIM:155950, MIM:163950, MIM:115150

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiofaciocutaneous syndrome 3	Definitive	Autosomal dominant
cardiofaciocutaneous syndrome	Definitive	Autosomal dominant
Noonan syndrome with multiple lentigines	Strong	Autosomal dominant
Noonan syndrome	Limited	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Noonan syndrome	Limited	AD
Costello syndrome	Disputed	AD
Noonan syndrome with multiple lentigines	Limited	AD
cardiofaciocutaneous syndrome	Definitive	AD

Mondo (16): RASopathy (MONDO:0021060), cardiofaciocutaneous syndrome 3 (MONDO:0014113), melorheostosis (MONDO:0007970), obesity disorder (MONDO:0011122), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), Noonan syndrome 1 (MONDO:0008104), cardiofaciocutaneous syndrome (MONDO:0015280), cardiofaciocutaneous syndrome 1 (MONDO:0007265), Noonan syndrome (MONDO:0018997), vascular malformation (MONDO:0024291), Parkes Weber syndrome (MONDO:0700325), non-small cell lung carcinoma (MONDO:0005233), autism spectrum disorder (MONDO:0005258), squamous cell lung carcinoma (MONDO:0005097), Noonan syndrome with multiple lentigines (MONDO:0007893)

Orphanet (12): RASopathy (Orphanet:536391), Cardiofaciocutaneous syndrome (Orphanet:1340), Melorheostosis (Orphanet:2485), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Noonan syndrome (Orphanet:648), OBSOLETE: Angioosteohypertrophic syndrome (Orphanet:2346), Parkes Weber syndrome (Orphanet:90307), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

155 total (30 of 155 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000154	Wide mouth
HP:0000155	Oral ulcer
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000465	Webbed neck

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004635_28	Testicular germ cell tumor	8.000000e-13
GCST004713_8	Testicular germ cell tumor	1.000000e-10
GCST006085_88	Prostate cancer	4.000000e-10

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
D008557	Melorheostosis	C05.116.099.708.702.593
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
C535579	Cardiofaciocutaneous syndrome (supp.)
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL2111289 (PROTEIN FAMILY), CHEMBL2111351 (PROTEIN FAMILY), CHEMBL3587 (SINGLE PROTEIN), CHEMBL3885566 (PROTEIN FAMILY), CHEMBL4523703 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523740 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523755 (PROTEIN-PROTEIN INTERACTION), CHEMBL4742286 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

54 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 346,102 (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
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1614701	SELUMETINIB	4	10,221
CHEMBL2103875	TRAMETINIB	4	14,034
CHEMBL2146883	COBIMETINIB	4	9,422
CHEMBL3187723	BINIMETINIB	4	7,280
CHEMBL5416410	DASATINIB	4	655
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL3264002	AVUTOMETINIB	3	2,208
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL274654	ORANTINIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL105442	CI-1040	2
CHEMBL507361	MIRDAMETINIB	2
CHEMBL1097999	E-6201	2
CHEMBL1230609	FORETINIB	2
CHEMBL1236682	REFAMETINIB	2
CHEMBL1615025	TAK-733	2

Clinical evidence (CIViC)

Drug × variant × indication: 8 predictive associations from 8 curated evidence items; also 1 diagnostic, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
MAP2K1 Q56_V60del	Selumetinib	Ovarian Serous Carcinoma	Sensitivity/Response	CIViC C	EID1661
MAP2K1 C121S	Vemurafenib	Melanoma	Resistance	CIViC C	EID1602
MAP2K1 K57N	Selumetinib	Melanoma	Resistance	CIViC C	EID7709
MAP2K1 P124S	Vemurafenib + Dabrafenib	Melanoma	Resistance	CIViC C	EID7660
MAP2K1 Q56P	Vemurafenib	Melanoma	Resistance	CIViC C	EID4727
MAP2K1 K57N	Selumetinib	Lung Adenocarcinoma	Sensitivity/Response	CIViC D	EID2936
MAP2K1 P124S	Selumetinib	Melanoma	Resistance	CIViC D	EID12
MAP2K1 Q56P	Selumetinib	Melanoma	Resistance	CIViC D	EID13

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE7 family

Most potent curated ligand interactions (20 total), top 20:

Ligand	Action	Affinity	Parameter
trametinib	Inhibition	9.15	pIC50
cobimetinib	Negative	9.05	pIC50
GDC-0623	Inhibition	9.0	pKi
TAK-733	Inhibition	8.49	pIC50
MAP855	Inhibition	8.3	pIC50
E6201	Inhibition	8.28	pIC50
CH4987655	Inhibition	8.28	pIC50
zapnometinib	Inhibition	8.24	pIC50
mirdametinib	Inhibition	8.15	pIC50
selumetinib	Negative	7.92	pIC50
MEK inhibitor I	Inhibition	7.92	pIC50
binimetinib	Negative	7.92	pIC50
refametinib	Negative	7.72	pIC50
BI-847325	Inhibition	7.6	pIC50
compound 3 [PMID: 31804822]	Negative	7.0	pIC50
CI-1040	Negative	6.92	pKd
avutometinib	Inhibition	6.8	pIC50
nedometinib	Inhibition	6.61	pIC50
MEK inhibitor II	Inhibition	6.42	pIC50
MS432	Inhibition	5.82	pIC50

Binding affinities (BindingDB)

173 measured of 265 human assays (271 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[(3S,4S)-4-[8-[2-chloro-4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	1 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-[2-chloro-4-(4-cyclopropylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	1.5 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-[2-chloro-4-[(6-fluoro-2-pyridinyl)oxy]phenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	1.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
Staurosporine	KD	1.7 nM
1-[4-[8-[2-chloro-4-[[6-(hydroxymethyl)-2-pyridinyl]oxy]phenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	2 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-[2-chloro-4-[4-(hydroxymethyl)pyrimidin-2-yl]oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	2 nM	US-10011599: Compounds and compositions as inhibitors of MEK
3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)benzamide	IC50	2 nM	US-8575391: 5-substituted-2-phenylamino benzamides as MEK inhibitors
4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoroimidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	2.4 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-4-[8-[2-chloro-4-[4-(hydroxymethyl)pyrimidin-2-yl]oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	2.6 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-3-fluoro-4-[7-fluoro-2-methyl-8-(2-methyl-4-pyrimidin-2-yloxyphenyl)imidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	2.6 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[7-fluoro-8-[2-methoxy-4-(4-methylpyrimidin-2-yl)oxyphenyl]imidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	2.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
(3S,4S)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidine-1-carboxamide	IC50	2.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidine-1-carboxamide	IC50	3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
2-[(3S,4S)-4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]acetonitrile	IC50	3 nM	US-9227969: Compounds and compositions as inhibitors of MEK
2-[(4S)-4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]acetonitrile	IC50	3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[8-[2-chloro-4-[(1-methyl-2-oxo-3-pyridinyl)oxy]phenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidine-1-carboxamide	IC50	3.6 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	3.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
2-[(3S,4S)-3-fluoro-4-[7-fluoro-8-(2-methoxy-4-pyrimidin-2-yloxyphenyl)-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]acetonitrile	IC50	3.7 nM	US-9227969: Compounds and compositions as inhibitors of MEK
2-[(4S)-3-fluoro-4-[7-fluoro-8-(2-methoxy-4-pyrimidin-2-yloxyphenyl)-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]acetonitrile	IC50	3.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[8-[2-chloro-4-[(1-methyl-2-oxo-3-pyridinyl)oxy]phenyl]-7-fluoroimidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	3.8 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoroimidazo[4,5-c]quinolin-1-yl]-4-methylpiperidin-1-yl]-2-hydroxyethanone	IC50	4.3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[7-fluoro-8-[2-fluoro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-2-methylimidazo[4,5-c]quinolin-1-yl]piperidine-1-carboxamide	IC50	4.3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[8-[2-chloro-4-(4-methyl-3-oxopyrazin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidine-1-carboxamide	IC50	4.5 nM	US-9227969: Compounds and compositions as inhibitors of MEK
4-[8-[2-chloro-4-(4-methyl-3-oxopyrazin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	4.5 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[7-fluoro-8-(2-methoxy-4-pyrimidin-2-yloxyphenyl)imidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	4.6 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-4-[8-[2-chloro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	4.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	5 nM	US-9629836: Compounds and compositions as inhibitors of MEK
mirdametinib	IC50	5.2 nM	US-8575391: 5-substituted-2-phenylamino benzamides as MEK inhibitors
4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoroimidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	5.3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-3-fluoro-4-[7-fluoro-8-(2-methoxy-4-pyrimidin-2-yloxyphenyl)-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	5.7 nM	US-9227969: Compounds and compositions as inhibitors of MEK
1-[(4S)-3-fluoro-4-[7-fluoro-8-(2-methoxy-4-pyrimidin-2-yloxyphenyl)-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	5.7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-4-[8-[2-chloro-4-(5-fluoro-4-methylpyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	6.2 nM	US-9629836: Compounds and compositions as inhibitors of MEK
3-[3-chloro-4-[7-fluoro-1-[1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl]-2-methylimidazo[4,5-c]quinolin-8-yl]phenoxy]-1-methylpyridin-2-one	IC50	7 nM	US-9227969: Compounds and compositions as inhibitors of MEK
3-[3-chloro-4-[7-fluoro-1-[1-[(2S)-2-hydroxypropanoyl]-4-methylpiperidin-4-yl]-2-methylimidazo[4,5-c]quinolin-8-yl]phenoxy]-1-methylpyridin-2-one	IC50	7 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	7.1 nM	US-9629836: Compounds and compositions as inhibitors of MEK
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxo-1,2-oxazolidin-2-yl)methyl]benzamide	IC50	7.2 nM	US-8575391: 5-substituted-2-phenylamino benzamides as MEK inhibitors
(2S)-1-[(3S,4S)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxypropan-1-one	IC50	7.3 nM	US-9629836: Compounds and compositions as inhibitors of MEK
3-[3-chloro-4-[7-fluoro-1-[1-(2-hydroxyacetyl)piperidin-4-yl]-2-methylimidazo[4,5-c]quinolin-8-yl]phenoxy]-1-methylpyridin-2-one	IC50	8.5 nM	US-9629836: Compounds and compositions as inhibitors of MEK
1-[(3S,4S)-4-[8-[2-chloro-4-[(4-methoxy-1,3,5-triazin-2-yl)oxy]phenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone	IC50	8.5 nM	US-9629836: Compounds and compositions as inhibitors of MEK
5-[[acetyl(methoxy)amino]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide	IC50	8.6 nM	US-8575391: 5-substituted-2-phenylamino benzamides as MEK inhibitors
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide	IC50	8.8 nM	US-8575391: 5-substituted-2-phenylamino benzamides as MEK inhibitors
1-[(3S,4S)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-methoxyethanone	IC50	9 nM	US-9227969: Compounds and compositions as inhibitors of MEK
1-[(3S)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-methoxyethanone	IC50	9 nM	US-9629836: Compounds and compositions as inhibitors of MEK
4-[7-fluoro-8-[2-fluoro-4-(4-methylpyrimidin-2-yl)oxyphenyl]imidazo[4,5-c]quinolin-1-yl]-4-methylpiperidine-1-carboxamide	IC50	9.2 nM	US-9629836: Compounds and compositions as inhibitors of MEK
5-(2-fluoro-4-iodoanilino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	IC50	10 nM	US-8470837: MAPK/ERK kinase inhibitors
3-[(2S)-2,3-dihydroxypropyl]-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	IC50	10 nM	US-8470837: MAPK/ERK kinase inhibitors
6-fluoro-5-(2-fluoro-4-iodoanilino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	IC50	10 nM	US-8470837: MAPK/ERK kinase inhibitors
4-[[3-[(2S)-2,3-dihydroxypropyl]-6-fluoro-8-methyl-4,7-dioxopyrido[2,3-d]pyrimidin-5-yl]amino]-3-fluorobenzonitrile	IC50	10 nM	US-8470837: MAPK/ERK kinase inhibitors
5-(4-bromo-2-fluoroanilino)-3-[(2S)-2,3-dihydroxypropyl]-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	IC50	10 nM	US-8470837: MAPK/ERK kinase inhibitors
1-[4-[8-[2-chloro-4-(4-fluoropyrimidin-2-yl)oxyphenyl]-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]piperidin-1-yl]-2-hydroxyethanone	IC50	10 nM	US-9629836: Compounds and compositions as inhibitors of MEK

ChEMBL bioactivities

1678 potent at pChembl≥5 of 1794 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.82	IC50	0.015	nM	CHEMBL3819302
10.72	IC50	0.019	nM	CHEMBL3818677
9.70	EC50	0.2	nM	CHEMBL2087076
9.70	IC50	0.2	nM	COBIMETINIB
9.62	Kd	0.24	nM	RO-4987655
9.48	IC50	0.33	nM	MIRDAMETINIB
9.40	EC50	0.4	nM	CHEMBL2087080
9.40	EC50	0.4	nM	CHEMBL2087076
9.40	Kd	0.4	nM	MIRDAMETINIB
9.32	IC50	0.48	nM	TRAMETINIB
9.30	IC50	0.5	nM	CHEMBL3819622
9.28	IC50	0.52	nM	TRAMETINIB
9.22	EC50	0.6	nM	CHEMBL2087461
9.22	IC50	0.6	nM	CHEMBL450775
9.15	IC50	0.7	nM	TRAMETINIB
9.15	IC50	0.7	nM	CHEMBL5433950
9.05	EC50	0.9	nM	CHEMBL2087462
9.05	EC50	0.9	nM	CHEMBL2087461
9.05	IC50	0.9	nM	COBIMETINIB
9.05	IC50	0.9	nM	CHEMBL450775
9.04	IC50	0.92	nM	TRAMETINIB
9.03	IC50	0.93	nM	STAUROSPORINE
9.00	IC50	1	nM	BOSUTINIB
9.00	IC50	1	nM	CHEMBL3946736
9.00	IC50	1	nM	ARCTIGENIN
9.00	IC50	1	nM	MIRDAMETINIB
9.00	IC50	1	nM	CHEMBL106489
8.96	IC50	1.1	nM	CHEMBL29714
8.96	EC50	1.1	nM	CHEMBL2087462
8.92	IC50	1.2	nM	CHEMBL244488
8.89	EC50	1.3	nM	CHEMBL2087082
8.85	IC50	1.4	nM	CHEMBL3182051
8.82	EC50	1.5	nM	CHEMBL2087081
8.82	IC50	1.5	nM	CHEMBL3980017
8.79	IC50	1.63	nM	CHEMBL3261161
8.77	IC50	1.7	nM	CHEMBL3930250
8.75	IC50	1.79	nM	TAK-733
8.74	IC50	1.8	nM	CHEMBL2146893
8.74	IC50	1.81	nM	PIMASERTIB
8.74	IC50	1.8	nM	CHEMBL3746640
8.74	IC50	1.8	nM	TRAMETINIB
8.71	IC50	1.95	nM	CHEMBL3261161
8.70	IC50	2	nM	CHEMBL244488
8.70	IC50	2	nM	CHEMBL3943311
8.70	IC50	2	nM	CHEMBL4588064
8.70	IC50	2	nM	TRAMETINIB
8.70	IC50	2	nM	CHEMBL5789143
8.70	IC50	2	nM	CHEMBL105642
8.70	IC50	2	nM	CHEMBL105220
8.70	IC50	2	nM	CHEMBL102374

PubChem BioAssay actives

1095 with measured affinity, of 3636 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
N-[2-[[6-[4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]piperazin-1-yl]-6-oxohexyl]amino]ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide	1307774: Inhibition of purified MEK1 (unknown origin) assessed as reduction in phosphorylation of inactive Erk2 incubated for 30 mins by Kinase-Glo luminescent kinase assay	ic50	<0.0001	uM
N-[2-[2-[2-[2-[4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide	1307774: Inhibition of purified MEK1 (unknown origin) assessed as reduction in phosphorylation of inactive Erk2 incubated for 30 mins by Kinase-Glo luminescent kinase assay	ic50	<0.0001	uM
N-(2-aminoethoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide	1307774: Inhibition of purified MEK1 (unknown origin) assessed as reduction in phosphorylation of inactive Erk2 incubated for 30 mins by Kinase-Glo luminescent kinase assay	ic50	<0.0001	uM
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide	578978: Binding affinity to MEK1 by surface plasmon resonance in presence of ATP	kd	0.0002	uM
Cobimetinib	689334: Inhibition of MEK-mediated ERK T202/Y204 phosphorylation in human MDA-MB-231T cells after 1 hr by immunoblotting	ic50	0.0002	uM
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1H-indazole-5-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0002	uM
N-[(2R)-2,3-dihydroxypropoxy]-4-(2-fluoro-4-iodoanilino)-1H-indazole-5-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0004	uM
mirdametinib	578978: Binding affinity to MEK1 by surface plasmon resonance in presence of ATP	kd	0.0004	uM
N-[2-[[2-[[6-[4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]piperazin-1-yl]-6-oxohexyl]amino]-2-oxoethyl]amino]ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide	1307774: Inhibition of purified MEK1 (unknown origin) assessed as reduction in phosphorylation of inactive Erk2 incubated for 30 mins by Kinase-Glo luminescent kinase assay	ic50	0.0005	uM
N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide	689335: Inhibition of MEK1-mediated ERK2 T202/Y204 phosphorylation using biotinylated MBP as substrate preincubated for 30 mins measured after 100 mins by cRAF-MEK-ERK enzyme coupled assay	ic50	0.0006	uM
7-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,2-benzothiazole-6-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0006	uM
Trametinib	1633263: Inhibition of MEK1 (unknown origin)	ic50	0.0007	uM
N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-8,8a-dihydropyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide	1996351: Inhibition of MEK1 (unknown origin)	ic50	0.0007	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2132083: Inhibition of MEK1 (unknown origin)	ic50	0.0009	uM
N-[(2R)-2,3-dihydroxypropoxy]-7-(2-fluoro-4-iodoanilino)-1,2-benzothiazole-6-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0009	uM
4-[3-chloro-4-(1,5-dimethylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0010	uM
Bosutinib	1301435: Inhibition of human MEK1 after 40 mins in presence of MgATP	ic50	0.0010	uM
(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-3-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-2-one	325818: Inhibition of MKK1	ic50	0.0010	uM
6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenylsulfanylanilino)quinoline-3-carbonitrile	63583: Inhibitory activity against Dual specificity mitogen-activated protein kinase kinase using coupled MEK assay (which uses activated Raf to activate an inactivate GST-MEK)	ic50	0.0011	uM
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide	298460: Inhibition of MEK assessed as inhibition of ERK phosphorylation by Raf-MEK-ERK cascade assay	ic50	0.0012	uM
N-ethoxy-4-(2-fluoro-4-iodoanilino)-1H-indazole-5-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0013	uM
N-(cyclopropylmethoxy)-4-(2-fluoro-4-iodoanilino)-1H-indazole-5-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0015	uM
2-[(2S)-2,3-dihydroxypropyl]-8-(2-fluoro-4-iodoanilino)pyrido[3,4-d]pyridazin-1-one	1141152: Inhibition of MEK1 (unknown origin)	ic50	0.0016	uM
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(propan-2-ylamino)methyl]azetidin-1-yl]methanone	689335: Inhibition of MEK1-mediated ERK2 T202/Y204 phosphorylation using biotinylated MBP as substrate preincubated for 30 mins measured after 100 mins by cRAF-MEK-ERK enzyme coupled assay	ic50	0.0018	uM
3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	1141152: Inhibition of MEK1 (unknown origin)	ic50	0.0018	uM
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide	1141153: Inhibition of MEK1 in human COLO205 cells	ic50	0.0018	uM
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-[3-[(sulfamoylamino)methyl]phenoxy]benzamide	1267606: Inhibition of MEK1 in human HeLa-MaTu matched pair cells assessed as reduction in ERK phosphorylation	ic50	0.0018	uM
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropoxy)benzamide	1524388: Inhibition of MEK1 (unknown origin)	ic50	0.0020	uM
4-[3-chloro-4-(1-methylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0020	uM
(4S,6Z,9S,10R,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	568315: Inhibition of human recombinant MEK1 expressed in insect cells after 20 mins	ic50	0.0020	uM
4-[3-bromo-4-(1-methylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0020	uM
4-[3-chloro-4-(1,4,5-trimethylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0020	uM
4-[3-chloro-4-(1-methylimidazol-2-yl)sulfanylanilino]-6-methoxy-7-[3-(1-oxo-1,4-thiazinan-4-yl)propoxy]quinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0020	uM
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0020	uM
6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyanilino)quinoline-3-carbonitrile	103032: Inhibition of ERK-phosphorylation by Raf-MEK-ERK in coupled ELISA	ic50	0.0024	uM
4-(4-benzylanilino)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile	63583: Inhibitory activity against Dual specificity mitogen-activated protein kinase kinase using coupled MEK assay (which uses activated Raf to activate an inactivate GST-MEK)	ic50	0.0027	uM
(4S,6Z,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	1336653: Inhibition of full length recombinant human His-tagged MEK1 expressed in baculovirus expression system after 1 hr by TR-FRET based LanthaScreen assay	ic50	0.0029	uM
(4E)-4-(2-amino-5-oxo-1H-imidazol-4-ylidene)-2-bromo-1,5,6,7-tetrahydropyrrolo[2,3-c]azepin-8-one	164360: Inhibition of kinase activity of Raf/MEK/ERK kinase cascade in ELISA	ic50	0.0030	uM
4-[3-chloro-4-(1-methylimidazol-2-yl)sulfanylanilino]-7-[3-(4-ethylpiperazin-1-yl)propoxy]-6-methoxyquinoline-3-carbonitrile	126772: Inhibitory concentration against Mitogen activated protein kinase kinase kinase 1 was determined using Raf/MEK1 coupled assay	ic50	0.0030	uM
4-[3-chloro-4-(1-methylimidazol-2-yl)sulfanylanilino]-7-[(E)-4-(diethylamino)but-1-enyl]-6-methoxyquinoline-3-carbonitrile	388639: Inhibition of MEK1 by raf/MEK1/MAPK coupled assay	ic50	0.0030	uM
3-[(2R)-2,3-dihydroxypropoxy]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	578436: Inhibition of MEK1 by IMAP assay	ic50	0.0031	uM
3-[(2S)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	578436: Inhibition of MEK1 by IMAP assay	ic50	0.0032	uM
3-(1,3-dihydroxypropan-2-yl)-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione	578436: Inhibition of MEK1 by IMAP assay	ic50	0.0033	uM
7-fluoro-6-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-benzofuran-5-carboxamide	1388885: Inhibition of MEK1 (unknown origin) using Ser/Thr 03 peptide substrate after 4 hrs by fluorescence assay	ic50	0.0034	uM
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1H-indazole-5-carboxamide	685222: Inhibition of MEK1-mediated ERK1 phosphorylation in human HCT116 cells after 2 hrs by immunoblotting method	ec50	0.0034	uM
N-[(2S)-2,3-dihydroxypropyl]-5-(2-fluoro-4-iodoanilino)pyrimidine-4-carboxamide	1141153: Inhibition of MEK1 in human COLO205 cells	ic50	0.0034	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507612: Binding affinity to MEK1	kd	0.0035	uM
4-(4-benzylanilino)-6,7-dimethoxyquinoline-3-carbonitrile	63583: Inhibitory activity against Dual specificity mitogen-activated protein kinase kinase using coupled MEK assay (which uses activated Raf to activate an inactivate GST-MEK)	ic50	0.0036	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148684: Binding affinity to human MAP2K1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0037	uM
3-[(2R)-2,3-dihydroxypropyl]-5-(2-fluoro-4-iodoanilino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7-dione	578436: Inhibition of MEK1 by IMAP assay	ic50	0.0038	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases activity, increases reaction, affects reaction, increases cleavage, increases abundance (+6 more)	13
sodium arsenite	increases abundance, increases activity, decreases reaction, increases phosphorylation, decreases expression (+3 more)	10
U 0126	decreases phosphorylation, decreases reaction, decreases activity, affects cotreatment, increases response to substance (+1 more)	9
Sorafenib	decreases reaction, decreases phosphorylation, decreases response to substance, increases phosphorylation, affects cotreatment	5
Resveratrol	decreases expression, decreases reaction, decreases activity, decreases phosphorylation, increases activity (+1 more)	5
Arsenic Trioxide	decreases phosphorylation, increases expression, decreases reaction, increases activity, increases phosphorylation (+2 more)	4
Estradiol	affects expression, increases activity, increases expression, decreases reaction	4
bisphenol A	decreases expression, decreases methylation	3
Air Pollutants	increases abundance, increases oxidation, affects expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	increases methylation, decreases reaction, affects cotreatment, increases phosphorylation, affects methylation	3
Cadmium	increases phosphorylation, decreases reaction, affects reaction, increases expression, increases activity	3
Doxorubicin	decreases reaction, increases cleavage, decreases expression, increases phosphorylation, affects reaction (+2 more)	3
Gallic Acid	decreases reaction, increases phosphorylation, affects binding, increases expression, affects cotreatment	3
Hydrogen Peroxide	increases activity, affects reaction, increases expression	3
Ozone	affects expression, decreases expression, decreases reaction, affects cotreatment, increases oxidation (+1 more)	3
Tetradecanoylphorbol Acetate	decreases activity, decreases reaction, increases expression, increases phosphorylation, increases reaction (+3 more)	3
Tretinoin	decreases reaction, increases activity, increases phosphorylation, increases reaction, affects cotreatment (+1 more)	3
Aflatoxin B1	increases expression, increases methylation	3
methylselenic acid	decreases expression, increases expression	2
trichostatin A	affects expression, affects cotreatment, decreases activity	2
cobaltous chloride	affects cotreatment, decreases activity, decreases reaction, increases activity, decreases response to substance (+1 more)	2
fludarabine	affects cotreatment, decreases reaction, increases cleavage, increases activity	2
sulindac sulfide	decreases phosphorylation, decreases reaction, increases activity, increases cleavage, increases expression (+1 more)	2
vanadyl sulfate	decreases reaction, increases phosphorylation, increases activity	2
deguelin	decreases expression	2
Vorinostat	affects cotreatment, decreases expression, decreases activity	2
Butyrates	affects cotreatment, decreases expression, decreases activity	2
Cannabidiol	affects cotreatment, increases expression, decreases expression, decreases reaction	2
Catechin	affects cotreatment, decreases reaction, increases phosphorylation, decreases expression, increases expression	2
Cisplatin	increases expression, increases phosphorylation, decreases response to substance, decreases activity, increases response to substance (+1 more)	2

ChEMBL screening assays

1200 unique, capped per target: 1150 binding, 47 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1042543	Binding	Inhibition of MEK1/2 phosphorylation in PMA-stimulated human U937 cells at 50 uM after 3 hrs by Western blotting	Structure-activity relationship (SAR) studies of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione: development of potential substrate-specific ERK1/2 inhibitors. — Bioorg Med Chem Lett
CHEMBL4124007	ADMET	Activation of MEK1/2 in EGF-stimulated human MDA-MB-231 cells assessed as increase in pERK1/2 levels preincubated for 30 mins followed by EGF stimulation measured after 15 mins by Western blot analysis relative to control	Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways. — Bioorg Med Chem Lett
CHEMBL645947	Functional	AP-1 suppression activity using freshly prepared DMSO stock	MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. — Bioorg Med Chem Lett

Cellosaurus cell lines

25 cell lines: 20 cancer cell line, 4 transformed cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_3084	OCUM-1	Cancer cell line	Female
CVCL_A221	Ma-Mel-86a	Cancer cell line	Female
CVCL_A222	Ma-Mel-86b	Cancer cell line	Female
CVCL_A4IM	VACO 432 MAP2K1 (-/-)	Cancer cell line	Male
CVCL_A7EV	PF130	Cancer cell line	Male
CVCL_B8JZ	Abcam HCT 116 MAP2K1 KO	Cancer cell line	Male
CVCL_B8YG	Abcam MCF-7 MAP2K1 KO	Cancer cell line	Female
CVCL_B9M8	Abcam A-549 MAP2K1 KO	Cancer cell line	Male
CVCL_C7TP	Ma-Mel-86c	Cancer cell line	Female
CVCL_C7TQ	Ma-Mel-86f	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients