Crystal Structure of Sphingosine Kinase 1 with PF-543

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Dec 18

PMID 25516793

Citations 41

Authors

Jing Wang

Stefan Knapp

Nigel J Pyne

Susan Pyne

Jonathan M Elkins

Affiliations

Soon will be listed here.

Abstract

The most potent inhibitor of Sphingosine Kinase 1 (SPHK1) so far identified is PF-543. The crystal structure of SPHK1 in complex with inhibitor PF-543 to 1.8 Å resolution reveals the inhibitor bound in a bent conformation analogous to that expected of a bound sphingosine substrate but with a rotated head group. The structural data presented will aid in the design of SPHK1 and SPHK2 inhibitors with improved properties.

Citing Articles

Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones.

Kruschel R, Malone K, Walsh A, Waeber C, McCarthy F Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006080 PMC: 11859825. DOI: 10.3390/ph18020268.

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

Sami Alkafaas S, Elsalahaty M, Ismail D, Ali Radwan M, Samy ElKafas S, Loutfy S Cancer Cell Int. 2024; 24(1):89.

PMID: 38419070 PMC: 10903003. DOI: 10.1186/s12935-024-03221-8.

Molecular docking analysis of sphingosine kinase 1 inhibitors for cancer management.

Barnawi J Bioinformation. 2023; 19(5):571-576.

PMID: 37886152 PMC: 10599685. DOI: 10.6026/97320630019571.

Host-Erythrocytic Sphingosine-1-Phosphate Regulates Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation.

Sah R, Anand S, Dar W, Jain R, Kumari G, Madan E Microbiol Spectr. 2023; :e0276622.

PMID: 36744922 PMC: 10100792. DOI: 10.1128/spectrum.02766-22.

Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer.

Gupta P, Kadamberi I, Mittal S, Tsaih S, George J, Kumar S Adv Sci (Weinh). 2022; 9(14):e2104452.

PMID: 35289120 PMC: 9108620. DOI: 10.1002/advs.202104452.

References

Pitson S, DAndrea R, Vandeleur L, Moretti P, Xia P, Gamble J . Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes. Biochem J. 2000; 350 Pt 2:429-41. PMC: 1221270. 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

Pyne N, Pyne S . Sphingosine 1-phosphate is a missing link between chronic inflammation and colon cancer. Cancer Cell. 2013; 23(1):5-7. DOI: 10.1016/j.ccr.2012.12.005. View

Sharma A, Sk U, Gimbor M, Hengst J, Wang X, Yun J . Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs. Eur J Med Chem. 2010; 45(9):4149-56. DOI: 10.1016/j.ejmech.2010.06.005. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Kohama T, Olivera A, Edsall L, Nagiec M, Dickson R, Spiegel S . Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem. 1998; 273(37):23722-8. DOI: 10.1074/jbc.273.37.23722. View

Chun J, Brinkmann V . A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med. 2011; 12(64):213-28. PMC: 3694567. View

Ding G, Sonoda H, Yu H, Kajimoto T, Goparaju S, Jahangeer S . Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J Biol Chem. 2007; 282(37):27493-27502. DOI: 10.1074/jbc.M701641200. View

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

10.

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

11.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

12.

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

13.

Savitsky P, Bray J, Cooper C, Marsden B, Mahajan P, Burgess-Brown N . High-throughput production of human proteins for crystallization: the SGC experience. J Struct Biol. 2010; 172(1):3-13. PMC: 2938586. DOI: 10.1016/j.jsb.2010.06.008. View

14.

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

15.

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

16.

Liang J, Nagahashi M, Kim E, Harikumar K, Yamada A, Huang W . Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013; 23(1):107-20. PMC: 3578577. DOI: 10.1016/j.ccr.2012.11.013. View

17.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

18.

Tonelli F, Lim K, Loveridge C, Long J, Pitson S, Tigyi G . FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells. Cell Signal. 2010; 22(10):1536-42. PMC: 2947314. DOI: 10.1016/j.cellsig.2010.05.022. View

19.

Plano D, Amin S, Sharma A . Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and recent developments in the synthesis of novel SphK inhibitors. J Med Chem. 2014; 57(13):5509-24. DOI: 10.1021/jm4011687. View

20.

Hengst J, Wang X, Sk U, Sharma A, Amin S, Yun J . Development of a sphingosine kinase 1 specific small-molecule inhibitor. Bioorg Med Chem Lett. 2010; 20(24):7498-502. DOI: 10.1016/j.bmcl.2010.10.005. View