TY - JOUR T1 - Antitumor Activity of Sphingosine Kinase Inhibitors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 596 LP - 603 DO - 10.1124/jpet.106.101345 VL - 318 IS - 2 AU - Kevin J. French AU - John J. Upson AU - Staci N. Keller AU - Yan Zhuang AU - Jong K. Yun AU - Charles D. Smith Y1 - 2006/08/01 UR - http://jpet.aspetjournals.org/content/318/2/596.abstract N2 - Sphingosine kinase (SK) is an oncogenic sphingolipid-metabolizing enzyme that catalyzes the formation of the mitogenic second messenger sphingosine-1-phosphate (S1P) at the expense of proapoptotic ceramide. Thus, SK is an attractive target for cancer therapy because blockage of S1P formation leads to inhibition of proliferation, as well as the induction of apoptosis in cancer cells. We have recently identified novel SK inhibitors with nanomolar to low micromolar potencies toward recombinant human SK. This study describes the continuing analysis of these inhibitors through in vitro and in vivo experiments. All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity. Blood and tumor inhibitor concentrations exceeded in vitro potency levels. Cell signaling analyses in vitro revealed mixed inhibition of mitogen-activated protein kinase kinase and Akt phosphorylation by the SK inhibitors. Importantly, 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) is orally bioavailable, detected in the blood for at least 8 h, and showed a significant inhibition of tumor growth in mice. These compounds are the first examples of nonlipid selective inhibitors of SK with in vivo antitumor activity and provide leads for further development of inhibitors of this important molecular target. The American Society for Pharmacology and Experimental Therapeutics ER -