Inhibitors of the sphingosine kinase pathway as potential therapeutics

Sphingosine kinase (SK) 1 and 2 are lipid kinases that phosphorylate sphingosine to form sphingosine-1 phosphate, a potent signalling molecule with pleiotrophic effects. SK1 is commonly up-regulated in tumours and its inhibition or genetic ablation has been shown to slow tumour growth as well as sensitise cancer cells to other chemotherapeutics. Therefore, SK1 is of particular interest as a target therapeutic intervention in cancer. Initial SK inhibitors were sphingosine derivatives and displayed efficacy in a number of disease models, establishing a premise for SK inhibition for anti-proliferative and anti-inflammatory therapies, even though these compounds had questionable specificity. More recently, a number of new SK inhibitors have been developed that display higher affinities and greater specificity for the SKs. Here we summarise the current small molecule inhibitors and related approaches for targeting the SKs, and their in vitro and in vivo efficacy. Furthermore, we highlight findings demonstrating the success of SK inhibition in cancer and a range of other disease models that promotes the continued interest in targeting the SKs for therapeutic benefit.M. R. Pitman and S. M. Pitso