Target Information
Target General Information | Top | |||||
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Target ID |
T04773
(Former ID: TTDR00808)
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Target Name |
Stromal cell-derived factor 1 (CXCL12)
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Synonyms |
hSDF-1; SDF1B; SDF1A; SDF1; SDF-1; Pre-B cell growth-stimulating factor; Pre-B cell growth stimulating factor; PBSF; Intercrine reduced in hepatomas; IRH; HIRH; C-X-C motif chemokine 12
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Gene Name |
CXCL12
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
2 | Heart failure [ICD-11: BD10-BD1Z] | |||||
Function |
Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Also binds to atypical chemokine receptor ACKR3, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. Binds to the allosteric site (site 2) of integrins and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 in a CXCR4-independent manner. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and ACKR3, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of ACKR3 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation. Stimulates the proliferation of bone marrow-derived B-cell progenitors in the presence of IL7 as well as growth of stromal cell-dependent pre-B-cells. Chemoattractant active on T-lymphocytes and monocytes but not neutrophils.
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BioChemical Class |
Cytokine: CXC chemokine
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UniProt ID | ||||||
Sequence |
MNAKVVVVLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIV
ARLKNNNRQVCIDPKLKWIQEYLEKALNKRFKM Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T45KYV |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
1 | Dociparstat sodium | Drug Info | Phase 3 | Acute myeloid leukaemia | [2] | |
2 | MyoCell SDF-1 | Drug Info | Phase 3 | Heart failure | [3] | |
3 | SDF-1 | Drug Info | Phase 2 | Heart failure | [4] | |
4 | NOX-A12 | Drug Info | Phase 1 | Macular degeneration | [5] | |
5 | REC-02 | Drug Info | Phase 1 | Congestive heart failure | [6] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | Dociparstat sodium | Drug Info | [7] | |||
2 | SDF-1 | Drug Info | [8] | |||
3 | NOX-A12 | Drug Info | [9] | |||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | MyoCell SDF-1 | Drug Info | [1] | |||
2 | REC-02 | Drug Info | [6] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: 1-Phenyl-3-[4-(1h-Tetrazol-5-Yl)phenyl]urea | Ligand Info | |||||
Structure Description | Crystal structure of CXCL12 in complex with inhibitor | PDB:4UAI | ||||
Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [10] |
PDB Sequence |
KPVSLSYRCP
10 CRFFESHVAR20 ANVKHLKILN30 TPNCALQIVA40 RLKNNNRQVC50 IDPKLKWIQE 60 YLEKALNK
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Click to View More Binding Site Information of This Target with Different Ligands |
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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Cytokine-cytokine receptor interaction | hsa04060 | Affiliated Target |
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Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
Viral protein interaction with cytokine and cytokine receptor | hsa04061 | Affiliated Target |
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Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
Chemokine signaling pathway | hsa04062 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
NF-kappa B signaling pathway | hsa04064 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Axon guidance | hsa04360 | Affiliated Target |
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Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
Leukocyte transendothelial migration | hsa04670 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Intestinal immune network for IgA production | hsa04672 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
Click to Show/Hide the Information of Affiliated Human Pathways |
Degree | 17 | Degree centrality | 1.83E-03 | Betweenness centrality | 1.66E-03 |
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Closeness centrality | 2.41E-01 | Radiality | 1.42E+01 | Clustering coefficient | 1.62E-01 |
Neighborhood connectivity | 3.94E+01 | Topological coefficient | 8.52E-02 | Eccentricity | 11 |
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 |
References | Top | |||||
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REF 1 | Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine. Expert Opin Biol Ther. 2011 Feb;11(2):189-97. | |||||
REF 2 | ClinicalTrials.gov (NCT04571645) Dociparstat (DSTAT) in Combination With Standard Chemotherapy for the Treatment of Acute Myeloid Leukemia (AML) (DASH AML). U.S. National Institutes of Health. | |||||
REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021307) | |||||
REF 4 | ClinicalTrials.gov (NCT01643590) Study to Evaluate the Safety and Efficacy of JVS-100 Administered to Adults With Ischemic Heart Failure.. U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT01194934) NOX-A12 Multiple Ascending Dose Study in Healthy Volunteers. U.S. National Institutes of Health. | |||||
REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 7 | Clinical pipeline report, company report or official report of Chimerix. | |||||
REF 8 | SDF-1 in myocardial repair. Gene Ther. 2012 Jun;19(6):583-7. | |||||
REF 9 | SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy. Transpl Int. 2015 Dec;28(12):1426-35. | |||||
REF 10 | Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine. J Med Chem. 2014 Nov 26;57(22):9693-9. |
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