Drugging Sphingosine Kinases

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2014 Nov 11

PMID 25384187

Citations 38

Authors

Webster L Santos

Kevin R Lynch

Affiliations

Soon will be listed here.

Abstract

The transfer of the gamma phosphate from ATP to sphingosine (Sph) to generate a small signaling molecule, sphingosine 1-phosphate (S1P), is catalyzed by sphingosine kinases (SphK), which exist as two isoforms, SphK1 and SphK2. SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio. Increases in S1P levels have been linked to diseases including sickle cell disease, cancer, and fibrosis. Therefore, SphKs are potential targets for drug discovery. However, the current chemical biology toolkit needed to validate these enzymes as drug targets is inadequate. With this review, we survey in vivo active SphK inhibitors and highlight the need for developing more potent and selective inhibitors.

Citing Articles

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Nagahashi M, Miyoshi Y Int J Mol Sci. 2024; 25(6).

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The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target.

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Untargeted lipidomics reveal association of elevated plasma C18 ceramide levels with reduced survival in metastatic castration-resistant prostate cancer patients.

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The Sphingolipid Inhibitors Ceranib-2 and SKI-II Reduce Measles Virus Replication in Primary Human Lymphocytes: Effects on mTORC1 Downstream Signaling.

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References

Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G . Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010; 9(11):883-97. DOI: 10.1038/nrd3248. View

Liu K, Guo T, Hait N, Allegood J, Parikh H, Xu W . Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a selective sphingosine kinase-2 inhibitor and anticancer agent. PLoS One. 2013; 8(2):e56471. PMC: 3577900. DOI: 10.1371/journal.pone.0056471. View

Lynch K . Building a better sphingosine kinase-1 inhibitor. Biochem J. 2012; 444(1):e1-2. DOI: 10.1042/BJ20120567. View

Kunkel G, Maceyka M, Milstien S, Spiegel S . Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013; 12(9):688-702. PMC: 3908769. DOI: 10.1038/nrd4099. View

Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J . Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002; 296(5566):346-9. DOI: 10.1126/science.1070238. View

Nagahashi M, Kim E, Yamada A, Ramachandran S, Allegood J, Hait N . Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network. FASEB J. 2012; 27(3):1001-11. PMC: 3574288. DOI: 10.1096/fj.12-219618. View

Kawamori T, Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Bielawski J . Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 2008; 23(2):405-14. PMC: 2630788. DOI: 10.1096/fj.08-117572. View

Kharel Y, Mathews T, Gellett A, Tomsig J, Kennedy P, Moyer M . Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. Biochem J. 2011; 440(3):345-53. PMC: 3443603. DOI: 10.1042/BJ20110817. View

Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S . Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat. 2007; 112(1):41-52. DOI: 10.1007/s10549-007-9836-9. View

10.

Zemann B, Kinzel B, Muller M, Reuschel R, Mechtcheriakova D, Urtz N . Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood. 2005; 107(4):1454-8. DOI: 10.1182/blood-2005-07-2628. View

11.

Fitzpatrick L, Green C, Maines L, Smith C . Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2. Pharmacology. 2011; 87(3-4):135-43. DOI: 10.1159/000323911. View

12.

Peest U, Sensken S, Andreani P, Hanel P, Van Veldhoven P, Graler M . S1P-lyase independent clearance of extracellular sphingosine 1-phosphate after dephosphorylation and cellular uptake. J Cell Biochem. 2008; 104(3):756-72. DOI: 10.1002/jcb.21665. View

13.

Sato K, Malchinkhuu E, Horiuchi Y, Mogi C, Tomura H, Tosaka M . Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J Neurochem. 2007; 103(6):2610-9. DOI: 10.1111/j.1471-4159.2007.04958.x. View

14.

French K, Zhuang Y, Maines L, Gao P, Wang W, Beljanski V . Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010; 333(1):129-39. PMC: 2846016. DOI: 10.1124/jpet.109.163444. View

15.

Rex K, Jeffries S, Brown M, Carlson T, Coxon A, Fajardo F . Sphingosine kinase activity is not required for tumor cell viability. PLoS One. 2013; 8(7):e68328. PMC: 3702540. DOI: 10.1371/journal.pone.0068328. View

16.

French K, Upson J, Keller S, Zhuang Y, Yun J, Smith C . Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther. 2006; 318(2):596-603. DOI: 10.1124/jpet.106.101345. View

17.

Hait N, Allegood J, Maceyka M, Strub G, Harikumar K, Singh S . Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science. 2009; 325(5945):1254-7. PMC: 2850596. DOI: 10.1126/science.1176709. View

18.

Venkataraman K, Lee Y, Michaud J, Thangada S, Ai Y, Bonkovsky H . Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res. 2008; 102(6):669-76. PMC: 2659392. DOI: 10.1161/CIRCRESAHA.107.165845. View

19.

Mizugishi K, Yamashita T, Olivera A, Miller G, Spiegel S, Proia R . Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol. 2005; 25(24):11113-21. PMC: 1316977. DOI: 10.1128/MCB.25.24.11113-11121.2005. View

20.

Allende M, Sasaki T, Kawai H, Olivera A, Mi Y, van Echten-Deckert G . Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem. 2004; 279(50):52487-92. DOI: 10.1074/jbc.M406512200. View