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
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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.
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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] |
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). |
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