Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4Y9NQI)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)
• Synonyms: MAP kinase kinase 1; MAPKK 1; MKK1; EC 2.7.12.2; ERK activator kinase 1; MAPK/ERK kinase 1; MEK 1
• Gene Name: MAP2K1
• Related Disease:
  Cardiofaciocutaneous syndrome
  Cardiofaciocutaneous syndrome 1
  Cardiofaciocutaneous syndrome 3
  Noonan syndrome with multiple lentigines
  Costello syndrome
  Noonan syndrome
• UniProt ID: MP2K1_HUMAN
• PDB ID: 1S9J ; 2P55 ; 3DV3 ; 3DY7 ; 3E8N ; 3EQB ; 3EQC ; 3EQD ; 3EQF ; 3EQG ; 3EQH ; 3EQI ; 3MBL ; 3ORN ; 3OS3 ; 3PP1 ; 3SLS ; 3V01 ; 3V04 ; 3VVH ; 3W8Q ; 3WIG ; 3ZLS ; 3ZLW ; 3ZLX ; 3ZLY ; 3ZM4 ; 4AN2 ; 4AN3 ; 4AN9 ; 4ANB ; 4ARK ; 4LMN ; 4MNE ; 4U7Z ; 4U80 ; 4U81 ; 5BX0 ; 5EYM ; 5HZE ; 5YT3 ; 6NYB ; 6PP9 ; 6Q0J ; 6Q0T ; 6U2G ; 6V2W ; 6X2P ; 6X2S ; 6X2X ; 7B3M ; 7B7R ; 7B94 ; 7B9L ; 7F2X ; 7M0T ; 7M0U ; 7M0V ; 7M0W ; 7M0X ; 7M0Y ; 7M0Z ; 7MFD ; 7PQV ; 7UMB ; 7XLP ; 7XNC ; 8DGS ; 8DGT
• EC Number: 2.7.12.2
• Pfam ID: PF00069
• Sequence:
  MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
  GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
  CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
  REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
  SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
  GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
  IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV
• 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.
• Tissue Specificity: Widely expressed, with extremely low levels in brain.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  HIF-1 sig.ling pathway (hsa04066)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Oocyte meiosis (hsa04114)
  Autophagy - animal (hsa04140)
  Efferocytosis (hsa04148)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apoptosis (hsa04210)
  Cellular senescence (hsa04218)
  Vascular smooth muscle contraction (hsa04270)
  VEGF sig.ling pathway (hsa04370)
  Apelin sig.ling pathway (hsa04371)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF sig.ling pathway (hsa04668)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  GnRH sig.ling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Prolactin sig.ling pathway (hsa04917)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Relaxin sig.ling pathway (hsa04926)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Alcoholism (hsa05034)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Re.l cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Non-small cell lung cancer (hsa05223)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  Frs2-mediated activation (R-HSA-170968)
  Signal transduction by L1 (R-HSA-445144)
  Uptake and function of anthrax toxins (R-HSA-5210891)
  RAF activation (R-HSA-5673000)
  MAP2K and MAPK activation (R-HSA-5674135)
  Negative feedback regulation of MAPK pathway (R-HSA-5674499)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by MAP2K mutants (R-HSA-9652169)
  Signaling by RAF1 mutants (R-HSA-9656223)
  MAPK3 (ERK1) activation (R-HSA-110056)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiofaciocutaneous syndrome	DISZJKSC	Definitive	Autosomal dominant	[1]
Cardiofaciocutaneous syndrome 1	DISV4HQA	Definitive	Autosomal dominant	[2]
Cardiofaciocutaneous syndrome 3	DIS1TZIR	Definitive	Autosomal dominant	[3]
Noonan syndrome with multiple lentigines	DIS014D0	Strong	Autosomal dominant	[4]
Costello syndrome	DISXVJH3	Disputed	Autosomal dominant	[1]
Noonan syndrome	DIS7Q7DN	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Trametinib	DM2JGQ3	Approved	Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) decreases the response to substance of Trametinib.	[50]
U0126	DM31OGF	Investigative	Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) decreases the response to substance of U0126.	[50]

30 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the activity of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[18]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[20]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[22]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[23]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[24]
Ethacrynic acid	DM60QMR	Approved	Ethacrynic acid increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[27]
Fludarabine	DMVRLT7	Approved	Fludarabine increases the activity of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[29]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[39]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[41]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[43]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[45]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[45]
CI-1040	DMF3DZX	Investigative	CI-1040 decreases the activity of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[47]

21 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[21]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[25]
Adenosine	DMM2NSK	Approved	Adenosine increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[26]
Mercaptopurine	DMTM2IK	Approved	Mercaptopurine decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[30]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[32]
Adaphostin	DM16QSG	Phase 1	Adaphostin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[33]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[35]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[36]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[38]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[42]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[44]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[26]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[46]
PI-103	DMEK4TJ	Investigative	PI-103 increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[48]
Cyclic guanosine monophosphate	DMOU93V	Investigative	Cyclic guanosine monophosphate decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[49]
GW-5074	DMIHOYF	Investigative	GW-5074 increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1).	[37]

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