Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTOHFIY)

• DTT Name: Sphingosine kinase 1 (SPHK1)
• Synonyms: SPK 1; SPK; SPHK1; SK 1; Acetyltransferase SPHK1
• Gene Name: SPHK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: SPHK1_HUMAN
• TTD ID: T86014
• EC Number: EC 2.7.1.91
• Sequence:
  MDPAGGPRGVLPRPCRVLVLLNPRGGKGKALQLFRSHVQPLLAEAEISFTLMLTERRNHA
  RELVRSEELGRWDALVVMSGDGLMHEVVNGLMERPDWETAIQKPLCSLPAGSGNALAASL
  NHYAGYEQVTNEDLLTNCTLLLCRRLLSPMNLLSLHTASGLRLFSVLSLAWGFIADVDLE
  SEKYRRLGEMRFTLGTFLRLAALRTYRGRLAYLPVGRVGSKTPASPVVVQQGPVDAHLVP
  LEEPVPSHWTVVPDEDFVLVLALLHSHLGSEMFAAPMGRCAAGVMHLFYVRAGVSRAMLL
  RLFLAMEKGRHMEYECPYLVYVPVVAFRLEPKDGKGVFAVDGELMVSEAVQGQVHPNYFW
  MVSGCVEPPPSWKPQQMPPPEEPL
• 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.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Calcium signaling pathway (hsa04020)
  Sphingolipid signaling pathway (hsa04071)
  VEGF signaling pathway (hsa04370)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Phenoxodiol	DMBUJVX	Ovarian cancer	2C73	Phase 1/2	[2]
GSK618334	DMJPXZ4	Drug abuse	6C4G.1Z	Phase 1	[3]

11 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Methylbenzenesulfonamide derivative 1	DMUNME2	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-10	DM61SR0	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-11	DMIKAJC	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-12	DMNIKTA	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-13	DM1J2V8	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-14	DMZ02LA	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-16	DMMDJH8	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-17	DMVG7A5	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-6	DMBKNDE	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-7	DMQAC4K	N. A.	N. A.	Patented	[4]
PMID27539678-Compound-9	DM0Y5NU	N. A.	N. A.	Patented	[4]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
B-5354a	DM8I5UF	Arteriosclerosis	BD40	Terminated	[5]
F-12509A	DM3786U	Arteriosclerosis	BD40	Terminated	[6]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-543	DMC4UHD	Discovery agent	N.A.	Investigative	[7]
SK1-I	DMMYX7C	Discovery agent	N.A.	Investigative	[8]
VPC-94075	DM20AJ4	Vascular disease	BE2Z	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	7.48E-01	-0.01	-0.06

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Sphingosine kinase 1 (SPHK1) DME Info
• Gene Name: SPHK1

1 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sphingosine-1-phosphate	DMJCQKA	Acne vulgaris	ED80	Phase 1	[10]

References

• [1] SPHK1 Is a Novel Target of Metformin in Ovarian Cancer. Mol Cancer Res. 2019 Apr;17(4):870-881.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Sphingosine kinase 1 is a potential therapeutic target for nasopharyngeal carcinoma.Oncotarget. 2016 Dec 6;7(49):80586-80598.
• [4] Sphingosine kinase inhibitors: a review of patent literature (2006-2015).Expert Opin Ther Pat. 2016 Dec;26(12):1409-1416.
• [5] Characterization of B-5354c, a new sphingosine kinase inhibitor, produced by a marine bacterium. J Antibiot (Tokyo). 2000 Aug;53(8):759-64.
• [6] F-12509A, a new sphingosine kinase inhibitor, produced by a discomycete. J Antibiot (Tokyo). 2000 May;53(5):459-66.
• [7] 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.
• [8] A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008 Aug 15;112(4):1382-91.
• [9] 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).
• [10] Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem. 2003 Nov 28;278(48):47408-15.