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Leukemia. 2017 Mar;31(3):669-677. doi: 10.1038/leu.2016.244. Epub 2016 Aug 30.

Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation.

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Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
Department of Community and Environmental Medicine, School of Medicine, University of California, Irvine, CA, USA.
Institute of Pharmacology, University of Bern, Bern, Switzerland.
The Wellcome Trust Sanger Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Department of Chemistry, McGill University, Montréal, Québec, Canada.
Cancer Center and Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
Northport Veterans Affairs Medical Center, Northport, NY, USA.
Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.


The frequency of poor outcomes in relapsed leukemia patients underscores the need for novel therapeutic approaches. The Food and Drug Administration-approved immunosuppressant FTY720 limits leukemia progression by activating protein phosphatase 2A and restricting nutrient access. Unfortunately, FTY720 cannot be re-purposed for use in cancer patients due to on-target toxicity associated with S1P receptor activation at the elevated, anti-neoplastic dose. Here we show that the constrained azacyclic FTY720 analog SH-RF-177 lacks S1P receptor activity but maintains anti-leukemic activity in vitro and in vivo. SH-RF-177 was not only more potent than FTY720, but killed via a distinct mechanism. Phosphorylation is dispensable for FTY720's anti-leukemic actions. However, chemical biology and genetic approaches demonstrated that the sphingosine kinase 2 (SPHK2)-mediated phosphorylation of SH-RF-177 led to engagement of a pro-apoptotic target and increased potency. The cytotoxicity of membrane-permeant FTY720 phosphonate esters suggests that the enhanced potency of SH-RF-177 stems from its more efficient phosphorylation. The tight inverse correlation between SH-RF-177 IC50 and SPHK2 mRNA expression suggests a useful biomarker for SH-RF-177 sensitivity. In summary, these studies indicate that FTY720 analogs that are efficiently phosphorylated but fail to activate S1P receptors may be superior anti-leukemic agents compared to compounds that avoid cardiotoxicity by eliminating phosphorylation.

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