Sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) are the sole producers of sphingosine 1-phosphate (S1P). S1P is a potent signaling lipid shown to promote cellular survival, neovascularization, and angiogenesis—all hallmarks of cancer. Of the two kinases, SK2 is less understood in cellular pathophysiology, in part due to a lack of highly potent and selective inhibitors. Our goal is to investigate SK2 using small-molecule bisubstrate inhibitors designed to target both the sphingosine- and ATP-binding domains simultaneously. The scaffold of these molecules consists of an adenosine derivative and a sphingosine mimetic joined by an aliphatic linker (Figure 1). Currently, several lead compounds are being synthesized to optimize the linker; once the ideal length is determined, the sphingosine-competitive region of the inhibitors will be altered. Specifically, it will be replaced with compound <b>VPC202147</b>, a highly selective substrate of SK2 that is phosphorylated at a level comparable to that of sphingosine. By inserting <b>VPC202147</b> into the substrate-competitive region (Figure 2), the potency and SK2-selectivity of such an inhibitor would increase dramatically.

Novel method for targeting sphingosine kinase 2: Design, synthesis, and evaluation of bisubstrate inhibitors

249th National Meeting (2015)

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