Target Information
Target General Information | Top | |||||
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Target ID |
T56697
(Former ID: TTDNC00370)
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Target Name |
Dickkopf-related protein 1 (DKK1)
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Synonyms |
hDkk1; hDkk-1; UNQ492/PRO1008; Dkk1; Dkk-1; Dickkopfrelated protein 1; Dickkopf1; Dickkopf-1
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Gene Name |
DKK1
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 9 Target-related Diseases | + | ||||
1 | Endometrial cancer [ICD-11: 2C76] | |||||
2 | Multiple myeloma [ICD-11: 2A83] | |||||
3 | Ovarian cancer [ICD-11: 2C73] | |||||
4 | Biliary tract cancer [ICD-11: 2C17] | |||||
5 | Esophageal cancer [ICD-11: 2B70] | |||||
6 | Liver cancer [ICD-11: 2C12] | |||||
7 | Oesophagogastric junction cancer [ICD-11: 2B71] | |||||
8 | Prostate cancer [ICD-11: 2C82] | |||||
9 | Low bone mass disorder [ICD-11: FB83] | |||||
Function |
DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease. Inhibits the pro-apoptotic function of KREMEN1 in a Wnt-independent manner, and has anti-apoptotic activity. Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.
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BioChemical Class |
Dickkopf protein
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UniProt ID | ||||||
Sequence |
MMALGAAGATRVFVAMVAAALGGHPLLGVSATLNSVLNSNAIKNLPPPLGGAAGHPGSAV
SAAPGILYPGGNKYQTIDNYQPYPCAEDEECGTDEYCASPTRGGDAGVQICLACRKRRKR CMRHAMCCPGNYCKNGICVSSDQNHFRGEIEETITESFGNDHSTLDGYSRRTTLSSKMYH TKGQEGSVCLRSSDCASGLCCARHFWSKICKPVLKEGQVCTKHRRKGSHGLEIFQRCYCG EGLSCRIQKDHHQASNSSRLHTCQRH Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T39XYV |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
1 | BHQ880 | Drug Info | Phase 2 | Multiple myeloma | [2], [3] | |
2 | DKN-01 | Drug Info | Phase 2 | Endometrial cancer | [4] | |
3 | PF-04840082 | Drug Info | Phase 1 | Osteoporosis | [5] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 2 Inhibitor drugs | + | ||||
1 | BHQ880 | Drug Info | [6] | |||
2 | DKN-01 | Drug Info | [7] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | PF-04840082 | Drug Info | [8] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Wnt signaling pathway | hsa04310 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy |
Degree | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 6.96E-06 |
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Closeness centrality | 1.92E-01 | Radiality | 1.33E+01 | Clustering coefficient | 4.09E-01 |
Neighborhood connectivity | 1.58E+01 | Topological coefficient | 2.46E-01 | Eccentricity | 13 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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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 Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | Wnt signaling pathway | |||||
NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
1 | TGF_beta_Receptor Signaling Pathway | |||||
2 | Wnt Signaling Pathway | |||||
3 | FSH Signaling Pathway | |||||
PID Pathway | [+] 5 PID Pathways | + | ||||
1 | Presenilin action in Notch and Wnt signaling | |||||
2 | Wnt signaling network | |||||
3 | Direct p53 effectors | |||||
4 | Regulation of nuclear beta catenin signaling and target gene transcription | |||||
5 | Validated targets of C-MYC transcriptional repression | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | TCF dependent signaling in response to WNT | |||||
2 | Negative regulation of TCF-dependent signaling by WNT ligand antagonists | |||||
WikiPathways | [+] 6 WikiPathways | + | ||||
1 | Mesodermal Commitment Pathway | |||||
2 | Endoderm Differentiation | |||||
3 | Differentiation Pathway | |||||
4 | Hair Follicle Development: Cytodifferentiation (Part 3 of 3) | |||||
5 | Primary Focal Segmental Glomerulosclerosis FSGS | |||||
6 | Cardiac Progenitor Differentiation |
References | Top | |||||
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REF 1 | Biological therapy for osteoporosis. Clin Calcium. 2014 Jun;24(6):919-25. | |||||
REF 2 | ClinicalTrials.gov (NCT01302886) Study of BHQ880 in Patients With High Risk Smoldering Multiple Myeloma. U.S. National Institutes of Health. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 5 | ClinicalTrials.gov (NCT01293487) Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men.. U.S. National Institutes of Health. | |||||
REF 6 | Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009 Jul 9;114(2):371-9. | |||||
REF 7 | The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer. Expert Opin Investig Drugs. 2020 Jul;29(7):639-644. | |||||
REF 8 | The application of target information and preclinical pharmacokinetic/pharmacodynamic modeling in predicting clinical doses of a Dickkopf-1 antibody for osteoporosis. J Pharmacol Exp Ther. 2010 Apr;333(1):2-13. |
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