Structure–Activity Relationships and Molecular Modeling of Sphingosine Kinase Inhibitors

Authors

Dong Jae Baek, CUNY Queens College
Neil MacRitchie, University of Strathclyde
Nahoum G. Anthony, University of Strathclyde
Simon P. Mackay, University of Strathclyde
Susan Pyne, University of Strathclyde
Nigel J. Pyne, University of Strathclyde
Robert Bittman, CUNY Queens CollegeFollow

Document Type

Article

Publication Date

October 2013

Abstract

The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure–activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.

Comments

This work was originally published in Journal of Medicinal Chemistry, available at doi:10.1021/jm401399c.