Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTROQ37)

• DTT Name: MAPK/ERK kinase kinase (MAP3K)
• Gene Name: MAP3K
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: NOUNIPROTAC
• TTD ID: T23003
• 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, leadingto 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.
• 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

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARRY-162	DM1P6FR	Melanoma	2C30	Approved	[2]
Trametinib	DM2JGQ3	Melanoma	2C30	Approved	[1]

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY 86-9766	DMPW5SB	Solid tumour/cancer	2A00-2F9Z	Phase 3	[3]
Selumetinib	DMC7W6R	Neurofibromatosis type 1	LD2D.10	Phase 3	[4]
E6201	DMOSL9P	Psoriasis vulgaris	EA90	Phase 2	[5]
MSC1936369B	DMH1DYU	Colorectal cancer	2B91.Z	Phase 2	[6]
PD-0325901	DM27D4J	Breast cancer	2C60-2C65	Phase 2	[2]
RO-5126766	DM3U9BY	Non-small-cell lung cancer	2C25	Phase 2	[7]
WX-554	DMRABOS	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[2]
ARRY-300	DMMPTCK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
BI-847325	DMY4B6J	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
RG7304	DMGFAVQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
TAK-733	DMC4RNA	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD8330	DMUKNQ5	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[2]
RG-7167	DMGLRK0	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[11]
RO-4987655	DMMF0OP	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[2]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CIP-137401	DMZ2WS9	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
G-573	DMC54UG	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
MEK inhibitor I	DMYJI90	Discovery agent	N.A.	Investigative	[12]
NSC-686549	DM0164B	Discovery agent	N.A.	Investigative	[13]
RO-4920506	DMD9SCI	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
SL-327	DMYJV4I	Discovery agent	N.A.	Investigative	[13]

References

• [1] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [2] MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
• [3] RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.Cancer Res.2009 Sep 1;69(17):6839-47.
• [4] Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59.
• [5] E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther. 2010 Oct;335(1):23-31.
• [6] Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013 Nov;133(9):2089-101.
• [7] The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells.PLoS One.2014 Nov 25;9(11):e113217.
• [8] MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 12;6:27.
• [9] doi: 10.1158/1535-7163.TARG-13-B281
• [10] Clinical pipeline report, company report or official report of Roche.
• [11] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2063).
• [12] Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg Med Chem Lett. 2004 Mar 22;14(6):1483-6.
• [13] A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8.