Target Information

Target General Information

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Target ID

T00496 (Former ID: TTDR01316)

Target Name

Prostate apoptosis response-4 (PAWR)

Synonyms

Prostate apoptosis response 4 protein; PRKC apoptosis WT1 regulator protein; PAR4

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Gene Name

PAWR

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Thrombosis [ICD-11: DB61-GB90]

Function

Pro-apoptopic protein capable of selectively inducing apoptosis in cancer cells, sensitizing the cells to diverse apoptotic stimuli and causing regression of tumors in animal models. Induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappa-B transcriptional activity. Inhibits the transcriptional activation and augments the transcriptional repression mediated by WT1. Down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1. Seems also to be a transcriptional repressor by itself. May be directly involved in regulating the amyloid precursor protein (APP) cleavage activity of BACE1.

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UniProt ID

PAWR_HUMAN

Sequence

MATGGYRTSSGLGGSTTDFLEEWKAKREKMRAKQNPPGPAPPGGGSSDAAGKPPAGALGT
PAAAAANELNNNLPGGAPAAPAVPGPGGVNCAVGSAMLTRAAPGPRRSEDEPPAASASAA
PPPQRDEEEPDGVPEKGKSSGPSARKGKGQIEKRKLREKRRSTGVVNIPAAECLDEYEDD
EAGQKERKREDAITQQNTIQNEAVNLLDPGSSYLLQEPPRTVSGRYKSTTSVSEEDVSSR
YSRTDRSGFPRYNRDANVSGTLVSSSTLEKKIEDLEKEVVRERQENLRLVRLMQDKEEMI
GKLKEEIDLLNRDLDDIEDENEQLKQENKTLLKVVGQLTR

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3D Structure

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AlphaFold

HIT2.0 ID

T69NNS

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

BMS-986141

Drug Info

Phase 2

Thrombosis

[2]

BMS-986120

Drug Info

Phase 1

Thrombosis

[3]

Mode of Action

[+] 1 Modes of Action

Antagonist

[+] 2 Antagonist drugs

BMS-986141

Drug Info

[4]

BMS-986120

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). 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 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).

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

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Prostate apoptosis response-4 (PAWR)		100.000 (340/340)	0.00E+00


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.

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	2.06E-05
Closeness centrality	2.13E-01	Radiality	1.37E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	2.50E+01	Topological coefficient	3.43E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

PAR-4 as a possible new target for pancreatic cancer therapy. Expert Opin Ther Targets. 2010 Jun;14(6):611-20.

REF 2

ClinicalTrials.gov (NCT02671461) Safety and Efficacy Study of a Protease Activated Receptor-4 Antagonist Being Tested to Reduce the Chances of Having Additional Strokes or Mini Strokes. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT02439190) CV004-007 Thrombosis Chamber Study. U.S. National Institutes of Health.

REF 4

Protease activated receptor 4 (PAR4) antagonists: Research progress on small molecules in the field of antiplatelet agents. Eur J Med Chem. 2021 Jan 1;209:112893.

REF 5

PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation. Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):448-456.

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