Sphingosine-1 phosphate (S1P) is a multifunctional signaling biomolecule that has been implicated in various diseases that include cancer, fibrosis, Alzheimer’s, and sickle cell disease. S1P is synthesized from the phosphorylation of sphingosine by sphingosine kinase 1 (SphK1) and 2 (SphK2). The two SphK isoforms differ with respect to their cellular localization and activity. SphK1 is bound to the cytoplasm and promotes cell survival. SphK2 is bound to the nucleus but can be relocated to the cytoplasm, and it promotes both cell survival and apoptosis. To help evaluate the role SphKs play in disease and assess their potential as therapeutic targets, it is essential to develop potent and selective inhibitors of SphK. We previously reported the development of the SphK1-selective inhibitor SLP7111228 (Ki = 48 nM, &gt; 200-fold SphK1 selectivity). Herein we report the design, synthesis, and biological evaluation of SLP7111228 derivatives containing aminothiazole tail-groups. These molecules display an unexpected potency and selectivity towards hSphK2, with hSphK2 Ki values as low as ~ 100 nM. Various analogs containing aryl-substituted aminothiazole tail-groups were synthesized, producing a structure-activity relationship study that examines substituent effects on the aryl-substituted aminothiazoles. Our studies suggest that electron-withdrawing substituents have a greater influence on the potency of our inhibitors than electron-donating substituents. Molecular modeling of select compounds will help elucidate the observed electronic influences on compound potency. The inhibitors’ in vitro activity in U937 cells and in vivo activity in mice will also be discussed.

Structure-activity relationship studies of guanidine-based aminothiazole inhibitors of sphingosine kinase

251st National Meeting (2016)

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