Elaboration and profiling of the first OSBP degrader issued from natural Schweinfurthins

We describe the two-step synthesis and in vitro validation of the first oxysterol-binding protein (OSBP) PROTAC deriving from a natural schweinfurthin (SW). SWs, like other families of natural molecules that target OSBP, have a specific cytotoxic profile related to an original mechanism of action and display promising anticancer properties. We elaborated a series of PROTACs and used the intrinsic fluorescence properties of the most cytotoxic one to confirm its direct interaction with OSBP, its rapid cellular penetration and its distinct cellular behavior from that of natural SWs. We then validated that this compound degrades OSBP via the UPS pathway and validated its specificity for OSBP compared with other ORP family proteins using proteomic analysis.