Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4TQBX)

• DTT Name: Extracellular signal-regulated kinase 2 (ERK2)
• Synonyms: PRKM2; PRKM1; P42-MAPK; P42 Mitogen-activated protein kinase; Mitogen-activated protein kinase 2; Mitogen-activated protein kinase 1; MAPK 2; MAPK 1; MAP kinase isoform p42; MAP kinase 2; MAP kinase 1; ERT1; ERK-2
• Gene Name: MAPK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: MK01_HUMAN
• TTD ID: T58970
• EC Number: EC 2.7.11.24
• Sequence:
  MAAAAAAGAGPEMVRGQVFDVGPRYTNLSYIGEGAYGMVCSAYDNVNKVRVAIKKISPFE
  HQTYCQRTLREIKILLRFRHENIIGINDIIRAPTIEQMKDVYIVQDLMETDLYKLLKTQH
  LSNDHICYFLYQILRGLKYIHSANVLHRDLKPSNLLLNTTCDLKICDFGLARVADPDHDH
  TGFLTEYVATRWYRAPEIMLNSKGYTKSIDIWSVGCILAEMLSNRPIFPGKHYLDQLNHI
  LGILGSPSQEDLNCIINLKARNYLLSLPHKNKVPWNRLFPNADSKALDLLDKMLTFNPHK
  RIEVEQALAHPYLEQYYDPSDEPIAEAPFKFDMELDDLPKEKLKELIFEETARFQPGYRS
• Function: MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the 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. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Phosphorylates CDK2AP2. Serine/threonine 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)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Dorso-ventral axis formation (hsa04320)
  TGF-beta signaling pathway (hsa04350)
  Axon guidance (hsa04360)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Gap junction (hsa04540)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  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)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling pathway (hsa04722)
  Retrograde endocannabinoid signaling (hsa04723)
  Glutamatergic synapse (hsa04724)
  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)
  Type II diabetes mellitus (hsa04930)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Alzheimer's disease (hsa05010)
  Prion diseases (hsa05020)
  Alcoholism (hsa05034)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  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:
  MAPK1 (ERK2) activation (R-HSA-112411)
  Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)
  ERK/MAPK targets (R-HSA-198753)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Oncogene Induced Senescence (R-HSA-2559585)
  FCERI mediated MAPK activation (R-HSA-2871796)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  NCAM signaling for neurite out-growth (R-HSA-375165)
  Recycling pathway of L1 (R-HSA-437239)
  CREB phosphorylation through the activation of Ras (R-HSA-442742)
  Activation of the AP-1 family of transcription factors (R-HSA-450341)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Negative regulation of FGFR3 signaling (R-HSA-5654732)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RAF/MAP kinase cascade (R-HSA-5673001)
  MAP2K and MAPK activation (R-HSA-5674135)
  Negative feedback regulation of MAPK pathway (R-HSA-5674499)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signal attenuation (R-HSA-74749)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  Gastrin-CREB signalling pathway via PKC and MAPK (R-HSA-881907)
  Growth hormone receptor signaling (R-HSA-982772)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DTT

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BVD-523	DMNB4XK	Melanoma	2C30	Phase 2	[2]
ASTX029	DMVZXIA	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[3]
HH2710	DM0C5MV	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
GDC-0994	DMFC2OY	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
JSI-1187	DMVJWBS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
LY3214996	DMFDAY7	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
VAN-10-4-eluting stent	DM3ZW6A	Artery stenosis	BD52	Phase 1	[8]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CHIR-99021	DMB8MNU	Allergic inflammation	4A80-4A85	Patented	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
COR-D	DMLXMCB	T-cell leukaemia	2A90	Preclinical	[10]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB220025	DMSBUET	Arthritis	FA20	Terminated	[11]

17 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(4-Fluoro-phenyl)-(9-methyl-9H-purin-6-yl)-amine	DMYAJQU	Discovery agent	N.A.	Investigative	[12]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[13]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[14]
AEZS-131	DMN9RE5	Solid tumour/cancer	2A00-2F9Z	Investigative	[15]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[1]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[16]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[1]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[17]
ERK inhibitor III	DMB3ROZ	Discovery agent	N.A.	Investigative	[18]
FR-180204	DM051PI	Discovery agent	N.A.	Investigative	[19]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[1]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[1]
Phosphonothreonine	DMTFHPI	Discovery agent	N.A.	Investigative	[11]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[1]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[20]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[1]
SCH772984	DMWVH62	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	6.78E-05	1.12	2.73

References

• [1] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [2] DOI: 10.1158/1538-7445.AM2015-4693
• [3] Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
• [4] Clinical pipeline report, company report or official report of HaiHe Biopharma.
• [5] ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors
• [6] National Cancer Institute Drug Dictionary (drug name JSI1187).
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.
• [9] Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95.
• [10] Corchorusin-D directed apoptosis of K562 cells occurs through activation of mitochondrial and death receptor pathways and suppression of AKT/PKB pathway. Cell Physiol Biochem. 2012;30(4):915-26.
• [11] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [12] Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22.
• [13] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [14] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [15] 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: 1495).
• [16] Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitum... J Med Chem. 2005 Sep 8;48(18):5639-43.
• [17] Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.
• [18] Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Bioorg Med Chem Lett. 2006 Dec 15;16(24):6281-7.
• [19] Crystal structure of human ERK2 complexed with a pyrazolo[3,4-c]pyridazine derivative. Bioorg Med Chem Lett. 2006 Jan 1;16(1):55-8.
• [20] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.
• [21] Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013 Jul;3(7):742-50.