Sphingosine kinase (SK) is an innovative molecular target for therapy because of its critical role in sphingolipid metabolism, which is known to regulate cell proliferation and activation. SK produces sphingosine-1-phosphate which promotes mitogenesis and concurrently depletes ceramide, thereby inhibiting apoptosis. SK can act as an oncogene, and is frequently overexpressed in a variety of human tumors.
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SK is also a critical mediator of the actions of inflammatory cytokines, such as TNFα, and angiogenic growth factors, such as VEGF. Furthermore, serum levels of sphingosine-1-phosphate are highly correlated with the incidence of cardiovascular disease. Therefore, inhibitors of SK are expected to have utility for the treatment of a variety of hyperproliferative, cardiovascular, inflammatory and angiogenic diseases.
Apogee Biotechnology Corporation novel sphingosine kinase inhibitors: (Lead compound, ABC294640)
- are the only “drug-like” SK inhibitors reported to date;
- do not inhibit a broad range of protein kinases;
- block signaling pathways required for VEGF- and TNFα-mediated cell activation;
- are orally bioavailable and have excellent pharmacokinetics;
- have an excellent safety profile;
- inhibit syngeneic and xenografted tumor growth in vivo;
- inhibit VEGF-induced vascular leakage in vivo;
- inhibit diabetes-induced retinal vascular leakage in vivo;
- inhibit collagen- and adjuvant-induced arthritis in vivo;
- inhibit DSS- and TNBS-induced inflammatory bowel disease in vivo;
- inhibit experimental lupus in vivo;
- inhibit liver ischemia-reperfusion injury in vivo; and
- inhibit kidney ischemia-reperfusion injury in vivo
- inhibit viral entry and replication
- inhibit lung inflammation and fibrosis.