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sphingosine kinase 2

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Target id: 2205

Nomenclature: sphingosine kinase 2

Abbreviated Name: SPHK2

Family: Sphingosine kinase

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 654 19q13.33 SPHK2 sphingosine kinase 2
Mouse - 617 7 B3 Sphk2 sphingosine kinase 2
Rat - 616 1q22 Sphk2 sphingosine kinase 2
Previous and Unofficial Names Click here for help
SK2
Database Links Click here for help
Alphafold Q9NRA0 (Hs), Q9JIA7 (Mm), Q6AYB2 (Rn)
BRENDA 2.7.1.91
CATH/Gene3D 3.40.50.10330
ChEMBL Target CHEMBL3023 (Hs), CHEMBL1075305 (Mm), CHEMBL1075197 (Rn)
Ensembl Gene ENSG00000063176 (Hs), ENSMUSG00000057342 (Mm), ENSRNOG00000021032 (Rn)
Entrez Gene 56848 (Hs), 56632 (Mm), 308589 (Rn)
Human Protein Atlas ENSG00000063176 (Hs)
KEGG Enzyme 2.7.1.91
KEGG Gene hsa:56848 (Hs), mmu:56632 (Mm), rno:308589 (Rn)
OMIM 607092 (Hs)
Pharos Q9NRA0 (Hs)
RefSeq Nucleotide NM_001204158 (Hs), NM_001172561 (Mm), NM_001012066 (Rn)
RefSeq Protein NP_064511 (Hs), NP_001166032 (Mm), NP_001012066 (Rn)
UniProtKB Q9NRA0 (Hs), Q9JIA7 (Mm), Q6AYB2 (Rn)
Wikipedia SPHK2 (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.1.91 Sphingosine + ATP = sphingosine 1-phosphate + ADP
dihydrosphingosine + ATP = dihydrosphingosine 1-phosphate + ADP
Cofactors Click here for help
Cofactor Species Comments Reference
Mg2+ None

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SLC4101431 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.1 pKi 2
⤷ pKi 7.1 (Ki 9x10-8 M) [2]
SLM6071469 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pKi 10
⤷ pKi 7.1 (Ki 8.9x10-8 M) [10]
Description: Biochemical assay using recombinant human SphK2.
MP-A08 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.2 pKi 6
⤷ pKi 5.2 (Ki 6.9x10-6 M) [6]
Description: In vitro inhibition of substrate phosphorylation.
SKI II Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.1 pKi 4
⤷ pKi 5.1 (Ki 7.9x10-6 M) [4]
opaganib Small molecule or natural product Primary target of this compound Hs Inhibition 5.0 pKi 3
⤷ pKi 5.0 (Ki 9.8x10-6 M) [3]
ROMe Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 4.8 pKi 5
⤷ pKi 4.8 (Ki 1.65x10-5 M) [5]
compound 49 [PMID: 30889352] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 1
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [1]
compound 59 [PMID: 30889352] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 1
⤷ pIC50 7.8 (IC50 1.7x10-8 M) [1]
compound 60 [PMID: 30889352] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.5 pIC50 1
⤷ pIC50 7.5 (IC50 3.1x10-8 M) [1]
compound 55 [PMID: 30889352] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.4 pIC50 1
⤷ pIC50 7.4 (IC50 4.1x10-8 M) [1]
compound 27d [PMID: 28231433] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 6.8 pIC50 9
⤷ pIC50 6.8 (IC50 1.45x10-7 M) [9]
PF-543 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.4 pIC50 9
⤷ pIC50 6.4 (IC50 3.56x10-7 M) [9]
ROMe Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 4.6 pIC50 5
⤷ pIC50 4.6 (IC50 2.7x10-5 M) [5]
Immunopharmacology Comments
The sphingosine kinases (SPHK1 and SPHK2; SK1, SK2) are key enzymes within the sphingolipid metabolism pathway that promote tumour growth and pathologic inflammation. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling, and is considered to be an anti-inflammatory enzyme with potential druggability for the treatment of autoimmune and inflammatory diseases [7]. Selective SK2 inhibitors are being used to explore the feasibility of targeting SK2 [8]. SK-2-selective inhibitors include Compound 27d [9], Compound 55, Compound 59, Compound 60 [1], SLM6071469 [10] and SLC4101431 [2]. Dual SK1/SK2 inhibitors include SLC4011540 [2], Compound 49 [1], MP-A08 [6] and SKI-II [3].

In 2020, in reponse to the SARS-CoV-2 pandemic, the SK2 inhibitor opaganib was evaluated (on compassionate grounds see NCT04435106) in patients with severe COVID-19 and hyperinflammation. Results have not yet been published but are available via the medRxiv preprint server (Kurd et al., Compassionate Use of Opaganib For Patients with Severe COVID-19; doi.org/10.1101/2020.06.20.20099010). Phase 2 study NCT04414618 was recruiting as of 23 June 2020.
Immuno Process Associations
Immuno Process:  Cellular signalling
Immuno Process:  Cytokine production & signalling
Immuno Process:  Immune regulation
Immuno Process:  Inflammation

References

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1. Adams DR, Tawati S, Berretta G, Rivas PL, Baiget J, Jiang Z, Alsfouk A, Mackay SP, Pyne NJ, Pyne S. (2019) Topographical Mapping of Isoform-Selectivity Determinants for J-Channel-Binding Inhibitors of Sphingosine Kinases 1 and 2. J Med Chem, 62 (7): 3658-3676. [PMID:30889352]

2. Childress ES, Kharel Y, Brown AM, Bevan DR, Lynch KR, Santos WL. (2017) Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity. J Med Chem, 60 (9): 3933-3957. [PMID:28406646]

3. French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD. (2010) Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther, 333 (1): 129-39. [PMID:20061445]

4. Gao P, Peterson YK, Smith RA, Smith CD. (2012) Characterization of isoenzyme-selective inhibitors of human sphingosine kinases. PLoS ONE, 7 (9): e44543. [PMID:22970244]

5. Lim KG, Sun C, Bittman R, Pyne NJ, Pyne S. (2011) (R)-FTY720 methyl ether is a specific sphingosine kinase 2 inhibitor: Effect on sphingosine kinase 2 expression in HEK 293 cells and actin rearrangement and survival of MCF-7 breast cancer cells. Cell Signal, 23 (10): 1590-5. [PMID:21620961]

6. Pitman MR, Powell JA, Coolen C, Moretti PA, Zebol JR, Pham DH, Finnie JW, Don AS, Ebert LM, Bonder CS et al.. (2015) A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties. Oncotarget, 6 (9): 7065-83. [PMID:25788259]

7. Pyne NJ, Adams DR, Pyne S. (2017) Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol Sci, 38 (7): 581-591. [PMID:28606480]

8. Pyne S, Adams DR, Pyne NJ. (2020) Sphingosine Kinases as Druggable Targets. Handb Exp Pharmacol, 259: 49-76. [PMID:29460151]

9. Schnute ME, McReynolds MD, Carroll J, Chrencik J, Highkin MK, Iyanar K, Jerome G, Rains JW, Saabye M, Scholten JA et al.. (2017) Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits. J Med Chem, 60 (6): 2562-2572. [PMID:28231433]

10. Sibley CD, Morris EA, Kharel Y, Brown AM, Huang T, Bevan DR, Lynch KR, Santos WL. (2020) Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity. J Med Chem, 63 (3): 1178-1198. [PMID:31895563]

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