Target Information

Target General Information

Target ID

T69085 (Former ID: TTDC00119)

Target Name

Transcription factor AP-1 (JUN)

Synonyms

V-jun avian sarcoma virus 17 oncogene homolog; Proto-oncogene c-jun; P39; C-jun proto-oncogene; Activator protein-1; Activator protein 1; AP1; AP-1 transcription factor

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Gene Name

JUN

Target Type

Discontinued target

[1]

Disease

[+] 1 Target-related Diseases

Rheumatoid arthritis [ICD-11: FA20]

Function

Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells. Binds to the USP28 promoter in colorectal cancer (CRC) cells. Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'.

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BioChemical Class

Basic leucine zipper bZIP

UniProt ID

JUN_HUMAN

Sequence

MTAKMETTFYDDALNASFLPSESGPYGYSNPKILKQSMTLNLADPVGSLKPHLRAKNSDL
LTSPDVGLLKLASPELERLIIQSSNGHITTTPTPTQFLCPKNVTDEQEGFAEGFVRALAE
LHSQNTLPSVTSAAQPVNGAGMVAPAVASVAGGSGSGGFSASLHSEPPVYANLSNFNPGA
LSSGGGAPSYGAAGLAFPAQPQQQQQPPHHLPQQMPVQHPRLQALKEEPQTVPEMPGETP
PLSPIDMESQERIKAERKRMRNRIAASKCRKRKLERIARLEEKVKTLKAQNSELASTANM
LREQVAQLKQKVMNHVNSGCQLMLTQQLQTF

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3D Structure

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AlphaFold

ADReCS ID

BADD_A02053 ; BADD_A02756 ; BADD_A05675 ; BADD_A06250 ; BADD_A06356 ; BADD_A08298

HIT2.0 ID

T26KIE

Drugs and Modes of Action

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Discontinued Drug(s)

[+] 1 Discontinued Drugs

T-5224

Drug Info

Discontinued in Phase 2

Rheumatoid arthritis

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 4 Inhibitor drugs

T-5224

Drug Info

[1]

PNRI-299

Drug Info

[3]

TAM-67

Drug Info

[4]

TWS-119

Drug Info

[5]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Transcription regulator protein BACH2 (BACH2)	PF00651 ; PF03131	40.984 (25/61)	1.12E-06
Transcription factor NF-E2 45 kDa subunit (NFE2)	PF03131	30.986 (22/71)	3.26E-06
Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1)	PF03131	38.333 (23/60)	8.38E-06
Nuclear factor erythroid 2-related factor 3 (NFE2L3)	PF03131	35.484 (22/62)	1.32E-05
Nuclear factor erythroid 2-related factor 2 (Nrf2)	PF03131	33.824 (23/68)	1.38E-05
Transcription regulator protein BACH1 (Bach1)	PF00651 ; PF03131	32.308 (21/65)	1.51E-05
X-box-binding protein 1 (XBP1)	PF07716	39.216 (20/51)	2.03E-04
Inactive histone-lysine N-methyltransferase 2E (KMT2E)	PF00628 ; PF00856	29.167 (28/96)	4.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
ErbB signaling pathway	hsa04012	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Mitophagy - animal	hsa04137	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Wnt signaling pathway	hsa04310	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Osteoclast differentiation	hsa04380	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
Focal adhesion	hsa04510	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Tight junction	hsa04530	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
NOD-like receptor signaling pathway	hsa04621	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
C-type lectin receptor signaling pathway	hsa04625	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
IL-17 signaling pathway	hsa04657	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th1 and Th2 cell differentiation	hsa04658	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th17 cell differentiation	hsa04659	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
B cell receptor signaling pathway	hsa04662	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
TNF signaling pathway	hsa04668	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neurotrophin signaling pathway	hsa04722	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
GnRH signaling pathway	hsa04912	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Estrogen signaling pathway	hsa04915	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Oxytocin signaling pathway	hsa04921	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Relaxin signaling pathway	hsa04926	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	101	Degree centrality	1.09E-02	Betweenness centrality	1.30E-02
Closeness centrality	2.76E-01	Radiality	1.47E+01	Clustering coefficient	9.78E-02
Neighborhood connectivity	3.93E+01	Topological coefficient	2.63E-02	Eccentricity	10
Download	Click to Download the Full PPI Network of This Target

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

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-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 34 KEGG Pathways	+
1	MAPK signaling pathway
2	ErbB signaling pathway
3	cAMP signaling pathway
4	Wnt signaling pathway
5	Osteoclast differentiation
6	Focal adhesion
7	Toll-like receptor signaling pathway
8	T cell receptor signaling pathway
9	B cell receptor signaling pathway
10	TNF signaling pathway
11	Neurotrophin signaling pathway
12	GnRH signaling pathway
13	Estrogen signaling pathway
14	Oxytocin signaling pathway
15	Non-alcoholic fatty liver disease (NAFLD)
16	Cocaine addiction
17	Amphetamine addiction
18	Epithelial cell signaling in Helicobacter pylori infection
19	Salmonella infection
20	Pertussis
21	Leishmaniasis
22	Chagas disease (American trypanosomiasis)
23	Hepatitis B
24	Influenza A
25	HTLV-I infection
26	Herpes simplex infection
27	Epstein-Barr virus infection
28	Pathways in cancer
29	Viral carcinogenesis
30	Colorectal cancer
31	Renal cell carcinoma
32	Choline metabolism in cancer
33	Inflammatory bowel disease (IBD)
34	Rheumatoid arthritis
NetPath Pathway	[+] 9 NetPath Pathways	+
1	IL-7 Signaling Pathway
2	IL1 Signaling Pathway
3	TCR Signaling Pathway
4	IL2 Signaling Pathway
5	IL4 Signaling Pathway
6	TSH Signaling Pathway
7	TGF_beta_Receptor Signaling Pathway
8	AndrogenReceptor Signaling Pathway
9	RANKL Signaling Pathway
Panther Pathway	[+] 13 Panther Pathways	+
1	Angiogenesis
2	Apoptosis signaling pathway
3	B cell activation
4	FAS signaling pathway
5	Huntington disease
6	Inflammation mediated by chemokine and cytokine signaling pathway
7	Oxidative stress response
8	PDGF signaling pathway
9	TGF-beta signaling pathway
10	T cell activation
11	Toll receptor signaling pathway
12	Ras Pathway
13	CCKR signaling map ST
Pathwhiz Pathway	[+] 2 Pathwhiz Pathways	+
1	Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
2	Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
PID Pathway	[+] 44 PID Pathways	+
1	Regulation of nuclear SMAD2/3 signaling
2	Fc-epsilon receptor I signaling in mast cells
3	Endothelins
4	BCR signaling pathway
5	RhoA signaling pathway
6	LPA receptor mediated events
7	CD40/CD40L signaling
8	Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
9	Calcineurin-regulated NFAT-dependent transcription in lymphocytes
10	Osteopontin-mediated events
11	Validated transcriptional targets of AP1 family members Fra1 and Fra2
12	Presenilin action in Notch and Wnt signaling
13	Integrin-linked kinase signaling
14	CDC42 signaling events
15	Signaling events regulated by Ret tyrosine kinase
16	Regulation of Telomerase
17	IL1-mediated signaling events
18	Glucocorticoid receptor regulatory network
19	IL2-mediated signaling events
20	Direct p53 effectors
21	Regulation of Androgen receptor activity
22	ErbB1 downstream signaling
23	ATF-2 transcription factor network
24	AP-1 transcription factor network
25	ErbB2/ErbB3 signaling events
26	IL6-mediated signaling events
27	PDGFR-beta signaling pathway
28	JNK signaling in the CD4+ TCR pathway
29	Nephrin/Neph1 signaling in the kidney podocyte
30	Validated nuclear estrogen receptor alpha network
31	PDGFR-alpha signaling pathway
32	Regulation of nuclear beta catenin signaling and target gene transcription
33	Signaling mediated by p38-alpha and p38-beta
34	Calcium signaling in the CD4+ TCR pathway
35	HIF-1-alpha transcription factor network
36	S1P2 pathway
37	Downstream signaling in na&#xef
38
39	FGF signaling pathway
40	RAC1 signaling pathway
41	Regulation of retinoblastoma protein
42	Signaling events mediated by focal adhesion kinase
43	FOXA1 transcription factor network
44	IL12 signaling mediated by STAT4
Reactome	[+] 6 Reactome Pathways	+
1	Pre-NOTCH Transcription and Translation
2	Oxidative Stress Induced Senescence
3	Senescence-Associated Secretory Phenotype (SASP)
4	FCERI mediated MAPK activation
5	Activation of the AP-1 family of transcription factors
6	MAPK6/MAPK4 signaling
WikiPathways	[+] 52 WikiPathways	+
1	Toll-like receptor signaling pathway
2	Estrogen signaling pathway
3	DNA Damage Response (only ATM dependent)
4	SIDS Susceptibility Pathways
5	TCR Signaling Pathway
6	ErbB Signaling Pathway
7	Senescence and Autophagy in Cancer
8	TGF Beta Signaling Pathway
9	IL-2 Signaling Pathway
10	Insulin Signaling
11	EGF/EGFR Signaling Pathway
12	Wnt Signaling Pathway
13	MAPK Cascade
14	Wnt Signaling Pathway and Pluripotency
15	MAPK Signaling Pathway
16	TGF beta Signaling Pathway
17	Copper homeostasis
18	FAS pathway and Stress induction of HSP regulation
19	Signaling of Hepatocyte Growth Factor Receptor
20	Focal Adhesion
21	Myometrial Relaxation and Contraction Pathways
22	Nuclear Receptors Meta-Pathway
23	Estrogen Receptor Pathway
24	Aryl Hydrocarbon Receptor Pathway
25	IL-3 Signaling Pathway
26	Hair Follicle Development: Cytodifferentiation (Part 3 of 3)
27	Selenium Metabolism and Selenoproteins
28	Pre-NOTCH Expression and Processing
29	Fc epsilon receptor (FCERI) signaling
30	Polycystic Kidney Disease Pathway
31	Apoptosis
32	PDGF Pathway
33	ATM Signaling Pathway
34	Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis
35	BDNF signaling pathway
36	Integrated Pancreatic Cancer Pathway
37	AGE/RAGE pathway
38	TNF alpha Signaling Pathway
39	B Cell Receptor Signaling Pathway
40	Prostate Cancer
41	Arylhydrocarbon receptor (AhR) signaling pathway
42	TWEAK Signaling Pathway
43	TSH signaling pathway
44	RANKL/RANK Signaling Pathway
45	Integrated Breast Cancer Pathway
46	IL-1 signaling pathway
47	MAPK targets/ Nuclear events mediated by MAP kinases
48	Apoptosis Modulation and Signaling
49	Physiological and Pathological Hypertrophy of the Heart
50	Regulation of toll-like receptor signaling pathway
51	Androgen receptor signaling pathway
52	IL-5 Signaling Pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016746)

REF 3

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1169-73.

REF 4

AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene. 2001 May 17;20(22):2771-80.

REF 5

Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat Chem Biol. 2005 Jul;1(2):74-84.

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