ARN14988 is a potent inhibitor of acid ceramidase (IC50 = 12.8 nM for the human enzyme). It inhibits acid ceramidase activity and increases levels of C16 dihydro ceramide and C16 ceramide in A375, G361, M14, MeWo, MNT-1, and SK-MEL-28 melanoma cells. ARN14988 also reduces growth of A375 and G361 melanoma cells (EC50s = 41.8 and 67.7 μM, respectively).
These sphingolipid-signaling inhibitors (FWARN398 = 307.27 g/mol;
FWARN14988 = 373.83 g/mol) target human acid ceramidase, with IC50 values
of 7.7 and 12.8 nM, respectively, thereby increasing cellular ceramide
levels and decreasing sphingosine 1-phosphate, and synergizing with
several antitumor agents. Compared to normal melanocytes, ceramide
production is suppressed in melanoma cells, and elevation of ceramide
levels enhances the cytotoxic effects of chemotherapeutic drugs on
proliferative melanoma cells in culture. ARN398 is unstable, showing a
plasma half-life of 1 min and an in vitro half-life of 120 min at pH 4.5.
ARN398 is more stable, showing a plasma half-life of 300 min and an in
vitro half-life of 140 min at pH 4.5.
