Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells.

Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine () is selective for SK2 whereas the 1-deoxysphinganines and are selective for SK1. (2,3)-1-Deoxysphinganine () induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitors and failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders.