Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUE7Z91)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)
• Synonyms: MAP kinase kinase 2; MAPKK 2; EC 2.7.12.2; ERK activator kinase 2; MAPK/ERK kinase 2; MEK 2
• Gene Name: MAP2K2
• Related Disease:
  Cardiofaciocutaneous syndrome
  Cardiofaciocutaneous syndrome 1
  Cardiofaciocutaneous syndrome 4
  Neurofibromatosis-Noonan syndrome
  Noonan syndrome
• UniProt ID: MP2K2_HUMAN
• PDB ID: 1S9I; 4H3Q
• EC Number: 2.7.12.2
• Pfam ID: PF00069
• Sequence:
  MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ
  KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ
  VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG
  LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ
  GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP
  PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL
  KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV
• Function: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases. 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.
• 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)
  HIF-1 sig.ling pathway (hsa04066)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  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)
  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)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  GnRH sig.ling pathway (hsa04912)
  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)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  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)
  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)
  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)
  MAPK1 (ERK2) activation (R-HSA-112411)

Molecular Interaction Atlas (MIA) of This DOT

5 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 4	DIS5D10S	Definitive	Autosomal dominant	[3]
Neurofibromatosis-Noonan syndrome	DISNOZ2M	Supportive	Autosomal dominant	[4]
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
Methotrexate	DM2TEOL	Approved	Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2) affects the response to substance of Methotrexate.	[38]
Afimoxifene	DMFORDT	Phase 2	Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2) decreases the response to substance of Afimoxifene.	[39]

17 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 2 (MAP2K2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[17]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[18]
Fludarabine	DMVRLT7	Approved	Fludarabine increases the activity of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[22]
T83193	DMHO29Y	Patented	T83193 decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[31]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[28]
U0126	DM31OGF	Investigative	U0126 decreases the activity of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[11]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[19]
Adenosine	DMM2NSK	Approved	Adenosine increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[6]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[25]
Adaphostin	DM16QSG	Phase 1	Adaphostin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[11]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[32]
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 2 (MAP2K2).	[33]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[20]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[35]
PI-103	DMEK4TJ	Investigative	PI-103 increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[36]
Cyclic guanosine monophosphate	DMOU93V	Investigative	Cyclic guanosine monophosphate decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[37]
GW-5074	DMIHOYF	Investigative	GW-5074 increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[29]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2).	[23]

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