Target Information

Target General Information

Target ID

T45182 (Former ID: TTDI01434)

Target Name

Progranulin (PGRN)

Synonyms

Proepithelin; PGRN; PEPI; PCDGF; PC cell-derived growth factor; Granulin precursor; Glycoprotein of 88 Kda; Glycoprotein 88; GP88; Epithelin precursor; Acrogranin

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Gene Name

GRN

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Frontotemporal dementia ICD-11: 6D83

Function

Secreted proteins that act as key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation. Functions as regulator of proteins trafficking to lysosome and activity of lysosomal enzymes. Facilitates also the acidification of lysosomes, causing degradation of mature CTSD by CTSB. In addition, functions as wound-related growth factor that acts directly on dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structure (By similarity). Also promotes epithelial cell proliferation by blocking TNF-mediated neutrophil activation preventing release of oxidants and proteases. Moreover, modulates inflammation in neuron by preserving neuron survival, axonal outgrowth and neuronal integrity.

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UniProt ID

GRN_HUMAN

Sequence

MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGP
CQVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNS
VGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCIT
PTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCC
SDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQ
SGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQAL
KRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGS
EIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQH
CCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQG
WACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQLL

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

DNL593

Drug Info

Phase 1/2

Frontotemporal dementia

[2]

PBFT02

Drug Info

Phase 1/2

Frontotemporal dementia

[3]

PR-006

Drug Info

Phase 1/2

Frontotemporal dementia

[4]

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

There is no similarity protein (E value < 0.005) for this target


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	4	Degree centrality	4.30E-04	Betweenness centrality	3.09E-04
Closeness centrality	2.04E-01	Radiality	1.36E+01	Clustering coefficient	1.67E-01
Neighborhood connectivity	2.15E+01	Topological coefficient	2.56E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res. 2014 Dec;2(12):1209-19.

REF 2

ClinicalTrials.gov (NCT05262023) A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension. U.S.National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT04747431) A Phase 1b Open-Label, Multicenter, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacodynamic Effects of a Single Dose of PBFT02 Delivered Into the Cisterna Magna of Adult Subjects With Frontotemporal Dementia and Mutations in the Progranulin Gene. U.S.National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT04408625) A Phase 1/2 Ascending Dose Study to Evaluate the Safety and Effects on Progranulin Levels of LY3884963 in Patients With Fronto-Temporal Dementia With Progranulin Mutations (FTD-GRN). U.S.National Institutes of Health.

REF 5

Clinical pipeline report, company report or official report of Denali

REF 6

Clinical pipeline report, company report or official report of Passage Bio

REF 7

Clinical pipeline report, company report or official report of Prevail Therapeutics

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