Sphingolipids are cell membrane constituents which can serve as signaling molecules that can determine cell fate. Ceramide (Cer) and Sphingosine (Sph) are two sphingolipids that have been established as pro-apoptotic lipids. Conversely, Sphingosine-1-phosphate (S1P), another sphingolipid, can provide pro-survival signaling through their specific G-protein coupled receptors. One of the enzymes responsible for maintaining the balance between Cer/Sph and S1P is Sphingosine Kinase 1 (SK1). SK1 phosphorylates Sphinto S1P. In many different cancer types, including colon, lung, breast and renal cancers SK1 mRNA and protein levels have been shown to be increased relative to normal tissue. Furthermore, it has been shown that overexpression of SK1 in cells can enhance resistance to cell death. Due to the increase in SK1 in cancer and the pro-proliferative effects of S1P, SK1 has become an interesting target for drug development. In collaboration with Dr. Rizzo’s group from the Department of Applied Mathematics and Statistics at Stony Brook University, we were able to take the structure of SK1 and dock over one million compounds to determine which compounds had the most favorable binding. For the first round of testing, 100 compounds were chosen which bound to the Sph binding pocket. From these compounds, 6 were found to inhibit ≥ 50%. We conducted a second round of docking with families of similar compounds from the top 6 in the first round. From the second round of docking, 106 compounds (about 18 from each of the 6 families) were chosen to be tested further. In this work, we have started testing the 106 compounds for their ability to inhibit SK1 activity.

Discovery of new sphingosine kinase 1 inhibitors

256th National Meeting (2018)

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