(S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity

William J. Valentine, Gyöngyi N. Kiss, Jianxiong Liu, Shuyu E, Mari Gotoh, Kimiko Murakami-Murofushi, Truc Chi Pham, Daniel L. Baker, Abby L. Parrill, Xuequan Lu, Chaode Sun, Robert Bittman, Nigel J. Pyne, Gabor Tigyi

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P 1 receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P 1 by depleting the functional S1P 1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P 1 (EC 50 20±3nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P 1,3,4 (K i 384nM, 39nM, and 1190nM, respectively) and a partial antagonist of S1P 2 , and S1P 5 . Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K i values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P 2 transcripts and traces of S1P 5 . (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

Original languageEnglish (US)
Pages (from-to)1543-1553
Number of pages11
JournalCellular Signalling
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2010

Fingerprint

Immunosuppressive Agents
Lysosphingolipid Receptors
((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid
sphingosine 1-phosphate
Fingolimod Hydrochloride
Camptothecin
Lymphopenia
Multiple Sclerosis
Epithelial Cells
Cell Membrane
Pharmacology
Enzymes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

(S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. / Valentine, William J.; Kiss, Gyöngyi N.; Liu, Jianxiong; E, Shuyu; Gotoh, Mari; Murakami-Murofushi, Kimiko; Pham, Truc Chi; Baker, Daniel L.; Parrill, Abby L.; Lu, Xuequan; Sun, Chaode; Bittman, Robert; Pyne, Nigel J.; Tigyi, Gabor.

In: Cellular Signalling, Vol. 22, No. 10, 01.10.2010, p. 1543-1553.

Research output: Contribution to journalArticle

Valentine, WJ, Kiss, GN, Liu, J, E, S, Gotoh, M, Murakami-Murofushi, K, Pham, TC, Baker, DL, Parrill, AL, Lu, X, Sun, C, Bittman, R, Pyne, NJ & Tigyi, G 2010, '(S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity', Cellular Signalling, vol. 22, no. 10, pp. 1543-1553. https://doi.org/10.1016/j.cellsig.2010.05.023
Valentine, William J. ; Kiss, Gyöngyi N. ; Liu, Jianxiong ; E, Shuyu ; Gotoh, Mari ; Murakami-Murofushi, Kimiko ; Pham, Truc Chi ; Baker, Daniel L. ; Parrill, Abby L. ; Lu, Xuequan ; Sun, Chaode ; Bittman, Robert ; Pyne, Nigel J. ; Tigyi, Gabor. / (S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. In: Cellular Signalling. 2010 ; Vol. 22, No. 10. pp. 1543-1553.
@article{e6e924489131474e9681f6d8a759298e,
title = "(S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity",
abstract = "FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P 1 receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P 1 by depleting the functional S1P 1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P 1 (EC 50 20±3nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P 1,3,4 (K i 384nM, 39nM, and 1190nM, respectively) and a partial antagonist of S1P 2 , and S1P 5 . Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K i values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P 2 transcripts and traces of S1P 5 . (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.",
author = "Valentine, {William J.} and Kiss, {Gy{\"o}ngyi N.} and Jianxiong Liu and Shuyu E and Mari Gotoh and Kimiko Murakami-Murofushi and Pham, {Truc Chi} and Baker, {Daniel L.} and Parrill, {Abby L.} and Xuequan Lu and Chaode Sun and Robert Bittman and Pyne, {Nigel J.} and Gabor Tigyi",
year = "2010",
month = "10",
day = "1",
doi = "10.1016/j.cellsig.2010.05.023",
language = "English (US)",
volume = "22",
pages = "1543--1553",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - (S)-FTY720-Vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity

AU - Valentine, William J.

AU - Kiss, Gyöngyi N.

AU - Liu, Jianxiong

AU - E, Shuyu

AU - Gotoh, Mari

AU - Murakami-Murofushi, Kimiko

AU - Pham, Truc Chi

AU - Baker, Daniel L.

AU - Parrill, Abby L.

AU - Lu, Xuequan

AU - Sun, Chaode

AU - Bittman, Robert

AU - Pyne, Nigel J.

AU - Tigyi, Gabor

PY - 2010/10/1

Y1 - 2010/10/1

N2 - FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P 1 receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P 1 by depleting the functional S1P 1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P 1 (EC 50 20±3nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P 1,3,4 (K i 384nM, 39nM, and 1190nM, respectively) and a partial antagonist of S1P 2 , and S1P 5 . Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K i values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P 2 transcripts and traces of S1P 5 . (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

AB - FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P 1 receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P 1 by depleting the functional S1P 1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P 1 (EC 50 20±3nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P 1,3,4 (K i 384nM, 39nM, and 1190nM, respectively) and a partial antagonist of S1P 2 , and S1P 5 . Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K i values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P 2 transcripts and traces of S1P 5 . (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

UR - http://www.scopus.com/inward/record.url?scp=77954514553&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954514553&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2010.05.023

DO - 10.1016/j.cellsig.2010.05.023

M3 - Article

VL - 22

SP - 1543

EP - 1553

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 10

ER -