Target Information
| Target General Information | Top | |||||
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| Target ID |
T86014
(Former ID: TTDI02179)
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| Target Name |
Sphingosine kinase 1 (SPHK1)
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| Synonyms |
SPK 1; SPK; SPHK1; SK 1; Acetyltransferase SPHK1
Click to Show/Hide
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| Gene Name |
SPHK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Ovarian cancer [ICD-11: 2C73] | |||||
| 2 | Psychoactive substances use disorder [ICD-11: 6C4G] | |||||
| Function |
Acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis. Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling leading to IL17 secretion. In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES inducion through p38 MAPK signaling pathway. Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity. In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA. Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions.
Click to Show/Hide
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.1.91
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| Sequence |
MDPAGGPRGVLPRPCRVLVLLNPRGGKGKALQLFRSHVQPLLAEAEISFTLMLTERRNHA
RELVRSEELGRWDALVVMSGDGLMHEVVNGLMERPDWETAIQKPLCSLPAGSGNALAASL NHYAGYEQVTNEDLLTNCTLLLCRRLLSPMNLLSLHTASGLRLFSVLSLAWGFIADVDLE SEKYRRLGEMRFTLGTFLRLAALRTYRGRLAYLPVGRVGSKTPASPVVVQQGPVDAHLVP LEEPVPSHWTVVPDEDFVLVLALLHSHLGSEMFAAPMGRCAAGVMHLFYVRAGVSRAMLL RLFLAMEKGRHMEYECPYLVYVPVVAFRLEPKDGKGVFAVDGELMVSEAVQGQVHPNYFW MVSGCVEPPPSWKPQQMPPPEEPL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T95Y0K | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Phenoxodiol | Drug Info | Phase 1/2 | Ovarian cancer | [2] | |
| 2 | GSK618334 | Drug Info | Phase 1 | Drug abuse | [3] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | B-5354a | Drug Info | Terminated | Arteriosclerosis | [4] | |
| 2 | F-12509A | Drug Info | Terminated | Arteriosclerosis | [5] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Phenoxodiol | Drug Info | [6] | |||
| Inhibitor | [+] 17 Inhibitor drugs | + | ||||
| 1 | GSK618334 | Drug Info | [7] | |||
| 2 | Methylbenzenesulfonamide derivative 1 | Drug Info | [8] | |||
| 3 | PMID27539678-Compound-10 | Drug Info | [8] | |||
| 4 | PMID27539678-Compound-11 | Drug Info | [8] | |||
| 5 | PMID27539678-Compound-12 | Drug Info | [8] | |||
| 6 | PMID27539678-Compound-13 | Drug Info | [8] | |||
| 7 | PMID27539678-Compound-14 | Drug Info | [8] | |||
| 8 | PMID27539678-Compound-16 | Drug Info | [8] | |||
| 9 | PMID27539678-Compound-17 | Drug Info | [8] | |||
| 10 | PMID27539678-Compound-6 | Drug Info | [8] | |||
| 11 | PMID27539678-Compound-7 | Drug Info | [8] | |||
| 12 | PMID27539678-Compound-9 | Drug Info | [8] | |||
| 13 | B-5354a | Drug Info | [9] | |||
| 14 | F-12509A | Drug Info | [5] | |||
| 15 | PF-543 | Drug Info | [10] | |||
| 16 | SK1-I | Drug Info | [11] | |||
| 17 | VPC-94075 | Drug Info | [12] | |||
| 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: Sphingosine | Ligand Info | |||||
| Structure Description | Crystal structure of Sphingosine Kinase 1 | PDB:3VZB | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [13] |
| PDB Sequence |
AMGSGVLPRP
14 CRVLVLLNPR24 GGKGKALQLF34 RSHVQPLLAE44 AEISFTLMLT54 ERRNHARELV 64 RSEELGRWDA74 LVVMSGDGLM84 HEVVNGLMER94 PDWETAIQKP104 LCSLPAGSGN 114 ALAASLNHYA124 GYEQVTNEDL134 LTNCTLLLCR144 RLLSPMNLLS154 LHTASGLRLF 164 SVLSLAWGFI174 ADVDLESEKY184 RRLGEMRFTL194 GTFLRLAALR204 TYRGRLAYLP 214 VGRVGSKTPA224 SPVVVQQGPV234 DAHLVPLEEP244 VPSHWTVVPD254 EDFVLVLALL 264 HSHLGSEMFA274 APMGRCAAGV284 MHLFYVRAGV294 SRAMLLRLFL304 AMEKGRHMEY 314 ECPYLVYVPV324 VAFRLEPKDG334 KGVFAVDGEL344 MVSEAVQGQV354 HPNYFWMVSG 364
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ASP81
4.275
GLY113
4.236
ALA115
4.824
LEU167
3.411
SER168
3.140
ALA170
4.371
PHE173
3.959
ILE174
3.811
VAL177
3.734
ASP178
2.997
PHE192
3.447
THR196
3.723
LEU259
4.232
LEU261
3.926
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| Ligand Name: PF-543 | Ligand Info | |||||
| Structure Description | Sphingosine kinase 1 in complex with PF-543 | PDB:4V24 | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [14] |
| PDB Sequence |
PRGVLPRPCR
102 VLVLLNPRGG112 KGKALQLFRS122 HVQPLLAEAE132 ISFTLMLTER142 RNHARELVRS 152 EELGRWDALV162 VMSGDGLMHE172 VVNGLMERPD182 WETAIQKPLC192 SLPAGSGNAL 202 AASLNHYAGY212 EQVTNEDLLT222 NCTLLLCRRL232 LSPMNLLSLH242 TASGLRLFSV 252 LSLAWGFIAD262 VDLESEKYRR272 LGEMRFTLGT282 FLRLAALRTY292 RGRLAYLPVG 302 RVGSKTPASG318 PVDAHLVPLE328 EPVPSHWTVV338 PDEDFVLVLA348 LLHSHLGSEM 358 FAAPMGRCAA368 GVMHLFYVRA378 GVSRAMLLRL388 FLAMEKGRHM398 EYECPYLVYV 408 PVVAFRLEPK418 DGKGVFAVDG428 ELMVSEAVQG438 QVHPNYFWMV448 S |
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ASP167
4.072
ALA201
4.769
LEU253
4.003
SER254
3.893
ALA256
4.088
PHE259
3.600
ILE260
3.483
VAL263
3.465
ASP264
2.505
PHE278
3.702
THR282
3.536
LEU286
4.436
LEU345
3.997
LEU347
3.714
LEU354
3.812
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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 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 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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Sphingolipid metabolism | hsa00600 | Affiliated Target |
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| Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Sphingolipid signaling pathway | hsa04071 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Phospholipase D signaling pathway | hsa04072 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| VEGF signaling pathway | hsa04370 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Apelin signaling pathway | hsa04371 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Fc gamma R-mediated phagocytosis | hsa04666 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 20 | Degree centrality | 2.15E-03 | Betweenness centrality | 4.55E-03 |
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| Closeness centrality | 2.14E-01 | Radiality | 1.38E+01 | Clustering coefficient | 2.16E-01 |
| Neighborhood connectivity | 1.49E+01 | Topological coefficient | 1.01E-01 | Eccentricity | 10 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
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| Target Poor or Non Binders | ||||||
| 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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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Sphingosine and sphingosine-1-phosphate metabolism | |||||
| KEGG Pathway | [+] 7 KEGG Pathways | + | ||||
| 1 | Sphingolipid metabolism | |||||
| 2 | Metabolic pathways | |||||
| 3 | Calcium signaling pathway | |||||
| 4 | Sphingolipid signaling pathway | |||||
| 5 | VEGF signaling pathway | |||||
| 6 | Fc gamma R-mediated phagocytosis | |||||
| 7 | Tuberculosis | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | TNFalpha Signaling Pathway | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Angiogenesis | |||||
| 2 | VEGF signaling pathway | |||||
| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | Fc-epsilon receptor I signaling in mast cells | |||||
| 2 | Beta3 integrin cell surface interactions | |||||
| 3 | S1P1 pathway | |||||
| 4 | Sphingosine 1-phosphate (S1P) pathway | |||||
| 5 | PDGFR-beta signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Sphingolipid de novo biosynthesis | |||||
| 2 | VEGFR2 mediated cell proliferation | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Signal Transduction of S1P Receptor | |||||
| 2 | Protein folding | |||||
| 3 | Sphingolipid Metabolism | |||||
| References | Top | |||||
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| REF 1 | SPHK1 Is a Novel Target of Metformin in Ovarian Cancer. Mol Cancer Res. 2019 Apr;17(4):870-881. | |||||
| REF 2 | ClinicalTrials.gov (NCT00382811) OVATURE (OVArian TUmor REsponse) A Phase III Study of Weekly Carboplatin With and Without Phenoxodiol in Patients With Platinum-Resistant, Recurrent Epithelial Ovarian Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT00513279) To Investigate If Single Doses Of GSK618334 Are Safe And To Investigate Blood Levels Of GSK618334. U.S. National Institutes of Health. | |||||
| REF 4 | B-535a, b and c, new sphingosine kinase inhibitors, produced by a marine bacterium; taxonomy, fermentation, isolation, physico-chemical properties and structure determination. J Antibiot (Tokyo). 2000 Aug;53(8):753-8. | |||||
| REF 5 | F-12509A, a new sphingosine kinase inhibitor, produced by a discomycete. J Antibiot (Tokyo). 2000 May;53(5):459-66. | |||||
| REF 6 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 7 | Sphingosine kinase 1 is a potential therapeutic target for nasopharyngeal carcinoma.Oncotarget. 2016 Dec 6;7(49):80586-80598. | |||||
| REF 8 | Sphingosine kinase inhibitors: a review of patent literature (2006-2015).Expert Opin Ther Pat. 2016 Dec;26(12):1409-1416. | |||||
| REF 9 | Characterization of B-5354c, a new sphingosine kinase inhibitor, produced by a marine bacterium. J Antibiot (Tokyo). 2000 Aug;53(8):759-64. | |||||
| REF 10 | Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012 May 15;444(1):79-88. | |||||
| REF 11 | A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008 Aug 15;112(4):1382-91. | |||||
| REF 12 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2204). | |||||
| REF 13 | Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure. 2013 May 7;21(5):798-809. | |||||
| REF 14 | Crystal Structure of Sphingosine Kinase 1 with PF-543. ACS Med Chem Lett. 2014 Oct 27;5(12):1329-33. | |||||
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