Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein

Schweinfurthins (SWs) are naturally occurring prenylated
stilbenes
with promising anticancer properties. They act through a novel mechanism
of action similar to that of other families of natural compounds.
Their known target, oxysterol-binding protein (OSBP), plays a crucial
role in controlling the intracellular distribution of cholesterol.
We synthesized 15 analogues of SWs and demonstrated for the first
time that their cytotoxicity as well as that of natural derivatives
correlates with their affinity for OSBP. Through this extensive SAR
study, we selected one synthetic analogue obtained in one step from
SW-G. Using its fluorescence properties, we showed that this compound
recapitulates the effect of natural SW-G in cells and confirmed that
it leads to cell death via the same mechanism. Finally,
after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived
glioblastoma xenograft model.