Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIDAPM)

• DTT Name: ERK activator kinase 1 (MEK1)
• Synonyms: PRKMK1; Mitogen-activated protein kinase kinase 1; MKK1; MEK 1; MAPKK 1; MAPK/ERKkinase 1; MAPK/ERK kinase 1; MAP kinase kinase 1; Dual specificity mitogen-activated protein kinase kinase 1
• Gene Name: MAP2K1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: MP2K1_HUMAN
• TTD ID: T35940
• EC Number: EC 2.7.12.2
• Sequence:
  MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
  GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
  CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
  REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
  SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
  GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
  IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV
• Function: 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. 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. Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  Oocyte meiosis (hsa04114)
  PI3K-Akt signaling pathway (hsa04151)
  Vascular smooth muscle contraction (hsa04270)
  Dorso-ventral axis formation (hsa04320)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Toll-like receptor signaling pathway (hsa04620)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF signaling pathway (hsa04668)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Serotonergic synapse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  GnRH signaling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Prion diseases (hsa05020)
  Alcoholism (hsa05034)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Renal 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)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  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)
  MAPK3 (ERK1) activation (R-HSA-110056)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Selumetinib	DMC7W6R	Neurofibromatosis type 1	LD2D.10	Phase 3	[1]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Diamidothiazole derivative 1	DM02V5Q	N. A.	N. A.	Patented	[2]
Pyridic ketone derivative 1	DM3GU7K	N. A.	N. A.	Patented	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RDEA-436	DM0ILRU	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[4]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[5]
4,5-Dibromo-1H-pyrrole-2-carboxylic acid amide	DMDM9UV	Discovery agent	N.A.	Investigative	[6]
5-phenylamino-4-cyano-3-hydroxy-isothiazole	DMX6R0H	Discovery agent	N.A.	Investigative	[7]
ALDISIN	DMS80DF	Discovery agent	N.A.	Investigative	[6]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[6]
OROIDIN	DMA2DQT	Discovery agent	N.A.	Investigative	[6]
PD98059	DMZC90M	Cardiac arrest	MC82	Investigative	[8]
REVERSINE	DMWDNOK	Discovery agent	N.A.	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	9.21E-06	0.16	0.52
Rectal cancer	2C82	Rectal colon tissue	6.84E-01	0.03	0.2
Melanoma	2C82	Skin	8.00E-01	-0.07	-0.15

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [3] MEK inhibitors in oncology: a patent review (2015-Present).Expert Opin Ther Pat. 2017 Aug;27(8):887-906.
• [4] Clinical pipeline report, company report or official report of MedKoo Biosciences.
• [5] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [6] Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). J Med Chem. 2002 Jan 17;45(2):529-32.
• [7] Discovery of 3-hydroxy-4-carboxyalkylamidino-5-arylamino-isothiazoles as potent MEK1 inhibitors. Bioorg Med Chem Lett. 2006 Aug 1;16(15):3975-80.
• [8] The MEK1 inhibitor PD98059 sensitizes C8161 melanoma cells to cisplatin-induced apoptosis. Melanoma Res. 2001 Feb;11(1):11-9.
• [9] Reversine increases the plasticity of lineage-committed mammalian cells. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10482-7.