Target Information
| Target General Information | Top | |||||
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| Target ID |
T58970
(Former ID: TTDR00372)
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| Target Name |
Extracellular signal-regulated kinase 2 (ERK2)
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| 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
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| Gene Name |
MAPK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Melanoma [ICD-11: 2C30] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 3 | Arteries/arterioles disorder [ICD-11: BD52] | |||||
| 4 | Pancreatic cancer [ICD-11: 2C10] | |||||
| 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.
Click to Show/Hide
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.24
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| Sequence |
MAAAAAAGAGPEMVRGQVFDVGPRYTNLSYIGEGAYGMVCSAYDNVNKVRVAIKKISPFE
HQTYCQRTLREIKILLRFRHENIIGINDIIRAPTIEQMKDVYIVQDLMETDLYKLLKTQH LSNDHICYFLYQILRGLKYIHSANVLHRDLKPSNLLLNTTCDLKICDFGLARVADPDHDH TGFLTEYVATRWYRAPEIMLNSKGYTKSIDIWSVGCILAEMLSNRPIFPGKHYLDQLNHI LGILGSPSQEDLNCIINLKARNYLLSLPHKNKVPWNRLFPNADSKALDLLDKMLTFNPHK RIEVEQALAHPYLEQYYDPSDEPIAEAPFKFDMELDDLPKEKLKELIFEETARFQPGYRS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A00142 ; BADD_A01238 ; BADD_A03834 ; BADD_A04520 ; BADD_A05554 ; BADD_A05675 ; BADD_A06414 ; BADD_A06440 ; BADD_A08298 | |||||
| HIT2.0 ID | T79WXA | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | BVD-523 | Drug Info | Phase 2 | Melanoma | [2] | |
| 2 | ASTX029 | Drug Info | Phase 1/2 | Solid tumour/cancer | [3] | |
| 3 | HH2710 | Drug Info | Phase 1/2 | Solid tumour/cancer | [4] | |
| 4 | GDC-0994 | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
| 5 | JSI-1187 | Drug Info | Phase 1 | Solid tumour/cancer | [6] | |
| 6 | LY3214996 | Drug Info | Phase 1 | Solid tumour/cancer | [7] | |
| 7 | VAN-10-4-eluting stent | Drug Info | Phase 1 | Artery stenosis | [8] | |
| Patented Agent(s) | [+] 1 Patented Agents | + | ||||
| 1 | CHIR-99021 | Drug Info | Patented | Graft rejection | [9] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | COR-D | Drug Info | Preclinical | T-cell leukaemia | [10] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | SB220025 | Drug Info | Terminated | Arthritis | [11], [12] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | BVD-523 | Drug Info | [13] | |||
| 2 | GDC-0994 | Drug Info | [16] | |||
| Inhibitor | [+] 24 Inhibitor drugs | + | ||||
| 1 | ASTX029 | Drug Info | [14] | |||
| 2 | HH2710 | Drug Info | [15] | |||
| 3 | JSI-1187 | Drug Info | [17] | |||
| 4 | LY3214996 | Drug Info | [7] | |||
| 5 | VAN-10-4-eluting stent | Drug Info | [18] | |||
| 6 | CHIR-99021 | Drug Info | [19] | |||
| 7 | SB220025 | Drug Info | [21] | |||
| 8 | (4-Fluoro-phenyl)-(9-methyl-9H-purin-6-yl)-amine | Drug Info | [22] | |||
| 9 | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [23] | |||
| 10 | 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [24] | |||
| 11 | AEZS-131 | Drug Info | [25] | |||
| 12 | Bisindolylmaleimide-I | Drug Info | [1] | |||
| 13 | BMS-536924 | Drug Info | [26] | |||
| 14 | CI-1040 | Drug Info | [1] | |||
| 15 | DEBROMOHYMENIALDISINE | Drug Info | [27] | |||
| 16 | ERK inhibitor III | Drug Info | [28] | |||
| 17 | FR-180204 | Drug Info | [29] | |||
| 18 | KN-62 | Drug Info | [1] | |||
| 19 | KT-5720 | Drug Info | [1] | |||
| 20 | Phosphonothreonine | Drug Info | [21] | |||
| 21 | RO-316233 | Drug Info | [1] | |||
| 22 | Ro-4396686 | Drug Info | [30] | |||
| 23 | Ro31-8220 | Drug Info | [1] | |||
| 24 | SCH772984 | Drug Info | [31] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | COR-D | Drug Info | [20] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. | |||||
| REF 2 | ClinicalTrials.gov (NCT03417739) A Phase II Study of BVD-523 in Metastatic Uveal Melanoma. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03520075) Study of ASTX029 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04198818) A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patient With Advanced Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT01875705) A Dose-Escalation Study of GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT04418167) JSI-1187-01 Monotherapy and in Combination With Dabrafenib for Advanced Solid Tumors With MAPK Pathway Mutations. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 8 | Drug-Eluting Stent for High Risk Patients. University of Strathclyde Glasgow. 2015 | |||||
| REF 9 | Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015).Expert Opin Ther Pat. 2017 Jun;27(6):657-666. | |||||
| REF 10 | ClinicalTrials.gov (NCT04022863) Ovarium Cancer Detection by TEP's and ctDNA. U.S. National Institutes of Health. | |||||
| REF 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. (Ligand id: 6038). | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010505) | |||||
| REF 13 | DOI: 10.1158/1538-7445.AM2015-4693 | |||||
| REF 14 | Clinical pipeline report, company report or official report of Astex Pharmaceuticals. | |||||
| REF 15 | Clinical pipeline report, company report or official report of HaiHe Biopharma. | |||||
| REF 16 | ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors | |||||
| REF 17 | National Cancer Institute Drug Dictionary (drug name JSI1187). | |||||
| REF 18 | WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting. | |||||
| REF 19 | 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. | |||||
| REF 20 | 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. | |||||
| REF 21 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 22 | Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22. | |||||
| REF 23 | Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. | |||||
| REF 24 | 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. | |||||
| REF 25 | 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). | |||||
| REF 26 | 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. | |||||
| REF 27 | Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21. | |||||
| REF 28 | 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. | |||||
| REF 29 | 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. | |||||
| REF 30 | Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. | |||||
| REF 31 | 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. | |||||
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