Topographical mapping of isoform-selectivity determinants for J-channel-binding inhibitors of sphingosine kinases 1 and 2

David R. Adams, Salha Tawati, Giacomo Berretta, Paula Lopez Rivas, Jessica Baiget, Zhong Jiang, Aisha Alsfouk, Simon P. MacKay, Nigel J. Pyne, Susan Pyne

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Sphingosine kinase enzymes (SK1 and SK2) catalyze the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding "J-channel" in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency.

Original languageEnglish
Pages (from-to)3658-3676
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number7
Early online date19 Mar 2019
Publication statusPublished - 11 Apr 2019


  • sphingosine kinase
  • SK1
  • SK2

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