Target Information

Target General Information

Target ID

T23276 (Former ID: TTDR00373)

Target Name

Extracellular signal-regulated kinase 1 (ERK1)

Synonyms

PRKM3; P44-MAPK; P44-ERK1; P44 Mitogen-activated protein kinase; Mitogen-activated protein kinase 3; Microtubule-associated protein-2 kinase; Microtubule-associated protein 2 kinase; MAPK 3; MAP kinase isoform p44; MAP kinase 3; Insulin-stimulated MAP2 kinase; ERT2; ERK-1

Gene Name

MAPK3

Target Type

Clinical trial target

[1]

Disease

[+] 4 Target-related Diseases

Melanoma [ICD-11: 2C30]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Arteries/arterioles disorder [ICD-11: BD52]

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, 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. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

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BioChemical Class

Kinase

UniProt ID

MK03_HUMAN

EC Number

EC 2.7.11.24

Sequence

MAAAAAQGGGGGEPRRTEGVGPGVPGEVEMVKGQPFDVGPRYTQLQYIGEGAYGMVSSAY
DHVRKTRVAIKKISPFEHQTYCQRTLREIQILLRFRHENVIGIRDILRASTLEAMRDVYI
VQDLMETDLYKLLKSQQLSNDHICYFLYQILRGLKYIHSANVLHRDLKPSNLLINTTCDL
KICDFGLARIADPEHDHTGFLTEYVATRWYRAPEIMLNSKGYTKSIDIWSVGCILAEMLS
NRPIFPGKHYLDQLNHILGILGSPSQEDLNCIINMKARNYLQSLPSKTKVAWAKLFPKSD
SKALDLLDRMLTFNPNKRITVEEALAHPYLEQYYDPTDEPVAEEPFTFAMELDDLPKERL
KELIFQETARFQPGVLEAP

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3D Structure

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PDB

ADReCS ID

BADD_A03834 ; BADD_A08298

HIT2.0 ID

T25NSJ

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 7 Clinical Trial Drugs

BVD-523

Drug Info

Phase 2

Melanoma

[2]

ASTX029

Drug Info

Phase 1/2

Solid tumour/cancer

[3]

HH2710

Drug Info

Phase 1/2

Solid tumour/cancer

[4]

ASN007

Drug Info

Phase 1

Solid tumour/cancer

[5]

GDC-0994

Drug Info

Phase 1

Solid tumour/cancer

[6]

JSI-1187

Drug Info

Phase 1

Solid tumour/cancer

[7]

VAN-10-4-eluting stent

Drug Info

Phase 1

Artery stenosis

[8]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

COR-D

Drug Info

Preclinical

T-cell leukaemia

[9]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 2 Modulator drugs

BVD-523

Drug Info

[1]

GDC-0994

Drug Info

[12]

Inhibitor

[+] 6 Inhibitor drugs

ASTX029

Drug Info

[10]

HH2710

Drug Info

[11]

ASN007

Drug Info

[5]

JSI-1187

Drug Info

[13]

VAN-10-4-eluting stent

Drug Info

[14]

6-[(E)-2-(4-Fluoro-phenyl)-vinyl]-9H-purine

Drug Info

[16]

Activator

[+] 1 Activator drugs

COR-D

Drug Info

[15]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 82 KEGG Pathways	+
1	MAPK signaling pathway
2	ErbB signaling pathway
3	Ras signaling pathway
4	Rap1 signaling pathway
5	cGMP-PKG signaling pathway
6	cAMP signaling pathway
7	Chemokine signaling pathway
8	HIF-1 signaling pathway
9	FoxO signaling pathway
10	Sphingolipid signaling pathway
11	Oocyte meiosis
12	mTOR signaling pathway
13	PI3K-Akt signaling pathway
14	Adrenergic signaling in cardiomyocytes
15	Vascular smooth muscle contraction
16	Dorso-ventral axis formation
17	TGF-beta signaling pathway
18	Axon guidance
19	VEGF signaling pathway
20	Osteoclast differentiation
21	Focal adhesion
22	Adherens junction
23	Gap junction
24	Signaling pathways regulating pluripotency of stem cells
25	Platelet activation
26	Toll-like receptor signaling pathway
27	NOD-like receptor signaling pathway
28	Natural killer cell mediated cytotoxicity
29	T cell receptor signaling pathway
30	B cell receptor signaling pathway
31	Fc epsilon RI signaling pathway
32	Fc gamma R-mediated phagocytosis
33	TNF signaling pathway
34	Circadian entrainment
35	Long-term potentiation
36	Neurotrophin signaling pathway
37	Retrograde endocannabinoid signaling
38	Glutamatergic synapse
39	Cholinergic synapse
40	Serotonergic synapse
41	Long-term depression
42	Regulation of actin cytoskeleton
43	Insulin signaling pathway
44	GnRH signaling pathway
45	Progesterone-mediated oocyte maturation
46	Estrogen signaling pathway
47	Melanogenesis
48	Prolactin signaling pathway
49	Thyroid hormone signaling pathway
50	Oxytocin signaling pathway
51	Type II diabetes mellitus
52	Aldosterone-regulated sodium reabsorption
53	Alzheimer's disease
54	Prion diseases
55	Alcoholism
56	Shigellosis
57	Salmonella infection
58	Pertussis
59	Leishmaniasis
60	Chagas disease (American trypanosomiasis)
61	Toxoplasmosis
62	Tuberculosis
63	Hepatitis C
64	Hepatitis B
65	Influenza A
66	Pathways in cancer
67	Viral carcinogenesis
68	Proteoglycans in cancer
69	Colorectal cancer
70	Renal cell carcinoma
71	Pancreatic cancer
72	Endometrial cancer
73	Glioma
74	Prostate cancer
75	Thyroid cancer
76	Melanoma
77	Bladder cancer
78	Chronic myeloid leukemia
79	Acute myeloid leukemia
80	Non-small cell lung cancer
81	Central carbon metabolism in cancer
82	Choline metabolism in cancer
NetPath Pathway	[+] 2 NetPath Pathways	+
1	IL5 Signaling Pathway
2	TCR Signaling Pathway
Panther Pathway	[+] 21 Panther Pathways	+
1	Alzheimer disease-amyloid secretase pathway
2	Angiogenesis
3	Apoptosis signaling pathway
4	B cell activation
5	EGF receptor signaling pathway
6	Endothelin signaling pathway
7	FGF signaling pathway
8	Inflammation mediated by chemokine and cytokine signaling pathway
9	Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade
10	Integrin signalling pathway
11	Interferon-gamma signaling pathway
12	Interleukin signaling pathway
13	PDGF signaling pathway
14	Parkinson disease
15	TGF-beta signaling pathway
16	T cell activation
17	Toll receptor signaling pathway
18	VEGF signaling pathway
19	Ras Pathway
20	Angiotensin II-stimulated signaling through G proteins and beta-arrestin
21	CCKR signaling map ST
PID Pathway	[+] 52 PID Pathways	+
1	Fc-epsilon receptor I signaling in mast cells
2	Endothelins
3	BCR signaling pathway
4	Signaling events mediated by PRL
5	ErbB4 signaling events
6	GMCSF-mediated signaling events
7	Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
8	S1P3 pathway
9	EPHB forward signaling
10	Osteopontin-mediated events
11	S1P4 pathway
12	Presenilin action in Notch and Wnt signaling
13	TRAIL signaling pathway
14	CDC42 signaling events
15	Signaling events regulated by Ret tyrosine kinase
16	Angiopoietin receptor Tie2-mediated signaling
17	S1P1 pathway
18	Regulation of Telomerase
19	Netrin-mediated signaling events
20	Role of Calcineurin-dependent NFAT signaling in lymphocytes
21	Glucocorticoid receptor regulatory network
22	Arf6 downstream pathway
23	mTOR signaling pathway
24	IL2-mediated signaling events
25	EGF receptor (ErbB1) signaling pathway
26	Ras signaling in the CD4+ TCR pathway
27	Ceramide signaling pathway
28	Integrins in angiogenesis
29	IFN-gamma pathway
30	ErbB1 downstream signaling
31	ATF-2 transcription factor network
32	ErbB2/ErbB3 signaling events
33	ALK1 signaling events
34	PDGFR-beta signaling pathway
35	Neurotrophic factor-mediated Trk receptor signaling
36	Syndecan-1-mediated signaling events
37	Retinoic acid receptors-mediated signaling
38	Nongenotropic Androgen signaling
39	CXCR3-mediated signaling events
40	VEGFR1 specific signals
41	Regulation of cytoplasmic and nuclear SMAD2/3 signaling
42	Signaling events mediated by Stem cell factor receptor (c-Kit)
43	Signaling events mediated by VEGFR1 and VEGFR2
44	Syndecan-2-mediated signaling events
45	Cellular roles of Anthrax toxin
46	S1P2 pathway
47	Trk receptor signaling mediated by the MAPK pathway
48	Downstream signaling in na&#xef
49
50	VEGFR3 signaling in lymphatic endothelium
51	Alpha-synuclein signaling
52	FGF signaling pathway
Reactome	[+] 26 Reactome Pathways	+
1	MAPK3 (ERK1) activation
2	RAF-independent MAPK1/3 activation
3	ISG15 antiviral mechanism
4	ERK/MAPK targets
5	Regulation of actin dynamics for phagocytic cup formation
6	Oxidative Stress Induced Senescence
7	Senescence-Associated Secretory Phenotype (SASP)
8	Oncogene Induced Senescence
9	FCERI mediated MAPK activation
10	Regulation of HSF1-mediated heat shock response
11	NCAM signaling for neurite out-growth
12	Activation of the AP-1 family of transcription factors
13	Thrombin signalling through proteinase activated receptors (PARs)
14	Negative regulation of FGFR1 signaling
15	Negative regulation of FGFR2 signaling
16	Negative regulation of FGFR3 signaling
17	Negative regulation of FGFR4 signaling
18	RHO GTPases Activate WASPs and WAVEs
19	RAF/MAP kinase cascade
20	MAP2K and MAPK activation
21	Negative feedback regulation of MAPK pathway
22	Negative regulation of MAPK pathway
23	Signal attenuation
24	Advanced glycosylation endproduct receptor signaling
25	Gastrin-CREB signalling pathway via PKC and MAPK
26	Growth hormone receptor signaling
WikiPathways	[+] 59 WikiPathways	+
1	Toll-like receptor signaling pathway
2	Serotonin Receptor 4/6/7 and NR3C Signaling
3	Serotonin Receptor 2 and ELK-SRF/GATA4 signaling
4	Serotonin HTR1 Group and FOS Pathway
5	TCR Signaling Pathway
6	Hypothetical Network for Drug Addiction
7	EPO Receptor Signaling
8	TGF Beta Signaling Pathway
9	Regulation of Actin Cytoskeleton
10	IL-2 Signaling Pathway
11	Insulin Signaling
12	MAPK Cascade
13	IL-4 Signaling Pathway
14	MAPK Signaling Pathway
15	IL-6 signaling pathway
16	Signaling of Hepatocyte Growth Factor Receptor
17	Kit receptor signaling pathway
18	TCA Cycle Nutrient Utilization and Invasiveness of Ovarian Cancer
19	IL-3 Signaling Pathway
20	Cardiac Hypertrophic Response
21	MAP kinase activation in TLR cascade
22	Fc epsilon receptor (FCERI) signaling
23	RAF/MAP kinase cascade
24	Structural Pathway of Interleukin 1 (IL-1)
25	Genes and (Common) Pathways Underlying Drug Addiction
26	Signal Transduction of S1P Receptor
27	PDGF Pathway
28	Alpha 6 Beta 4 signaling pathway
29	Spinal Cord Injury
30	BDNF signaling pathway
31	Integrated Pancreatic Cancer Pathway
32	Oncostatin M Signaling Pathway
33	Corticotropin-releasing hormone
34	Interleukin-11 Signaling Pathway
35	AGE/RAGE pathway
36	TNF alpha Signaling Pathway
37	Prostate Cancer
38	Signaling Pathways in Glioblastoma
39	TSLP Signaling Pathway
40	IL-9 Signaling Pathway
41	IL17 signaling pathway
42	Alzheimers Disease
43	IL-7 Signaling Pathway
44	TWEAK Signaling Pathway
45	FSH signaling pathway
46	Leptin signaling pathway
47	RANKL/RANK Signaling Pathway
48	IL-1 signaling pathway
49	Thrombin signalling through proteinase activated receptors (PARs)
50	Signaling by Insulin receptor
51	Signaling by FGFR
52	RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
53	L1CAM interactions
54	Advanced glycosylation endproduct receptor signaling
55	Apoptosis Modulation and Signaling
56	MicroRNAs in cardiomyocyte hypertrophy
57	Regulation of toll-like receptor signaling pathway
58	Osteopontin Signaling
59	IL-5 Signaling Pathway

References

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REF 1

DOI: 10.1158/1538-7445.AM2015-4693

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

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

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 7

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 8

Drug-Eluting Stent for High Risk Patients. University of Strathclyde Glasgow. 2015

REF 9

ClinicalTrials.gov (NCT04022863) Ovarium Cancer Detection by TEP's and ctDNA. U.S. National Institutes of Health.

REF 10

Clinical pipeline report, company report or official report of Astex Pharmaceuticals.

REF 11

Clinical pipeline report, company report or official report of HaiHe Biopharma.

REF 12

ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors

REF 13

National Cancer Institute Drug Dictionary (drug name JSI1187).

REF 14

WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.

REF 15

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 16

Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22.

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