Sphingosine kinases (SphK1, SphK2) synthesize sphingosine 1-phosphate (S1P), a bioactive lipid that controls egress of lymphocytes from secondary lymphoid tissues and may influence heart rate and endothelial barrier function. Changes in SphK protein levels by manipulation of their underlying mRNAs or genes implicates the enzyme in a bewildering variety of signaling cascades and disease processes. Such studies point to a need for drug-like SphK inhibitors both to understand S1P biology better and to learn whether interdicting SphK activity influences the course of pathologies in disease models. However, such chemical tools are lacking currently but are essential to inform decisions regarding human SphKs as potential therapeutic targets. We have lead SphK1 and SphK2 inhibitors that are potent and isotype selective. These compounds hit their targets in vivo and rapidly modulate circulating S1P levels, providing an excellent pharmacodynamic biomarker that indexes compound pharmacokinetics. Our platforms are tractable regarding synthetic manipulation and we have developed a powerful algorithm to winnow substandard compounds and thereby efficiently identify the most useful chemical probes. Our veteran team consists a medicinal chemist (Santos) and a pharmacologist (Lynch) who can build on this success rapidly to realize optimized SphK1 and SphK2 inhibitors. Specifically, we will improve, by iterative rounds of synthesis and testing, our inhibitor series to obtain highly potent (KI 10 nM) isotype selective (>100-fold) inhibitors that are sufficiently persistent in animals to permit once daily dosing. The compounds that we generate will afford researchers the opportunity to test rigorously the idea that modulation of S1P levels by inhibition of one (or both) SphK isotypes is a promising therapeutic strategy.
Sphingosine 1-phosphate (S1P) is a bioactive lipid that is implicated in diseases such as cancer, fibrosis, and Alzheimer's dementia. Blockade of S1P synthesis, by inhibiting sphingosine kinases (SphK1 and SphK2), is hypothesized to lead to chemotherapy for these diseases. We have the lead compounds to test this hypothesis and our preliminary studies demonstrate that circulating S1P levels decrease rapidly upon treatment with our inhibitors. The goal of our project is to make these compounds better and validate this enzyme as a drug target so that pharmaceutical companies will be motivated to pursue drug development programs of SphK inhibitors.
|Congdon, Molly D; Kharel, Yugesh; Brown, Anne M et al. (2016) Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors. ACS Med Chem Lett 7:229-34|
|Patwardhan, Neeraj N; Morris, Emily A; Kharel, Yugesh et al. (2015) Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors. J Med Chem 58:1879-99|
|Kharel, Yugesh; Morris, Emily A; Congdon, Molly D et al. (2015) Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels. J Pharmacol Exp Ther 355:23-31|
|Santos, Webster L; Lynch, Kevin R (2015) Drugging sphingosine kinases. ACS Chem Biol 10:225-33|
|Congdon, Molly D; Childress, Elizabeth S; Patwardhan, Neeraj N et al. (2015) Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors. Bioorg Med Chem Lett 25:4956-60|