From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure–Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4‑((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)

The
sphingosine kinase (SK) inhibitor, SKI-II, has been employed
extensively in biological investigations of the role of SK1 and SK2
in disease and has demonstrated impressive anticancer activity in
vitro and in vivo. However, interpretations of results using this
pharmacological agent are complicated by several factors: poor SK1/2
selectivity, additional activity as an inducer of SK1-degradation,
and off-target effects, including its recently identified capacity
to inhibit dihydroceramide desaturase-1 (Des1). In this study, we
have delineated the structure–activity relationship (SAR) for
these different targets and correlated them to that required for anticancer
activity and determined that Des1 inhibition is primarily responsible
for the antiproliferative effects of SKI-II and its analogues. In
the course of these efforts, a series of novel SK1, SK2, and Des1
inhibitors have been generated, including compounds with significantly
greater anticancer activity.