A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model

  • Chem Biol. 2006 Nov;13(11):1227-34. doi: 10.1016/j.chembiol.2006.09.017.
Shifeng Pan  1 ,  Yuan Mi ,  Charles Pally ,  Christian Beerli ,  Alice Chen ,  Danilo Guerini ,  Klaus Hinterding ,  Barbara Nuesslein-Hildesheim ,  Tove Tuntland ,  Sophie Lefebvre ,  Yi Liu ,  Wenqi Gao ,  Alan Chu ,  Volker Brinkmann ,  Christian Bruns ,  Markus Streiff ,  Catherine Cannet ,  Nigel Cooke ,  Nathanael Gray
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
PMID: 17114004 DOI: 10.1016/j.chembiol.2006.09.017
Abstract

FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR Inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.

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