Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors.

ABSTRACT: The sphingosine 1-phosphate (S1P) signaling pathway is an attractive target for pharmacological manipulation due to its involvement in cancer progression and immune cell chemotaxis. The synthesis of S1P is catalyzed by the action of sphingosine kinase 1 or 2 (SphK1 or SphK2) on sphingosine and ATP. While potent and selective inhibitors of SphK1 or SphK2 have been reported, development of potent dual SphK1/SphK2 inhibitors are still needed. Towards this end, we report the structure-activity relationship profiling of 2-(hydroxymethyl)pyrrolidine-based inhibitors with 22d being the most potent dual SphK1/SphK2 inhibitor (SphK1 K_i = 0.679 μM, SphK2 K_i = 0.951 μM) reported in this series. 22d inhibited the growth of engineered Saccharomyces cerevisiae and decreased S1P lev

SUBMITTER: Li H 

PROVIDER: S-EPMC8862572 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature