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

ABSTRACT: Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P_1-5) 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 K_i = 120 nM, hSphK2 K_i = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (K_i = 90 nM,

SUBMITTER: Childress ES 

PROVIDER: S-EPMC6047346 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature