Ki: SphK with a Ki of about 5 μmol/L

Safingol is a sphingosine and PKC kinases inhibitor.

Sphingosine 1-phosphate, a product of sphingosine kinases (SphK), mediates various biological processes including cell proliferation, differentiation, motility, and apoptosis. Protein kinase C (PKC), is a family of protein kinase enzymes involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues.

In vitro: Safingol was identified as a potent competitive inhibitor of SphK and had significant in-vitro anticancer activity. Safingol could increase the in-vitro antitumor effect of various chemotherapeutic agents including cisplatin, doxorubicin, and mitomycin C via enhancing chemotherapy induced apoptosis. It was also found that safingol alone induced cell death by autophagy. Safingol was also extensively studied as an inhibitor of PKC, although the Ki was higher than that for SphK [1].

In vivo: Previous studies found that although safingol showed limited single-agent activity in vivo, xenograft experiments had indicated that safingol could increase the antitumor activity of cisplatin without increasing toxicity [1].

Clinical trial: Previous clinical study showed that safingol could be safely administered in combination with cisplatin. As expected from preclinical data, the reversible dose-dependent hepatic toxicity was observed. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks [1].

Reference:
[1] Dickson MA, Carvajal RD, Merrill AH Jr, Gonen M, Cane LM, Schwartz GK.  A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin Cancer Res. 2011 Apr 15;17(8):2484-92.