Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity

Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule
that interacts with its five G-protein coupled receptors (S1P1–5) to regulate cell growth and survival and has been
implicated in a variety of diseases including cancer and sickle cell
disease. As the key mediators in the synthesis of S1P, sphingosine
kinase (SphK) isoforms 1 and 2 have attracted attention as viable
targets for pharmaceutical inhibition. In this article, we describe
the design, synthesis, and biological evaluation of aminothiazole-based
guanidine inhibitors of SphK. Surprisingly, combining features of
reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 Ki = 120 nM, hSphK2 Ki = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (Ki = 90 nM, 100-fold SphK2
selectivity). These compounds effectively decrease S1P levels in vitro.
In vivo administration of 20dd validated that inhibition
of SphK2 increases blood S1P levels.