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. 2025 Sep:164:108909.
doi: 10.1016/j.bioorg.2025.108909. Epub 2025 Aug 23.

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

Carole Guimard  1 , Gwenaëlle Jézéquel  1 , Anne-Sophie Gay  2 , Laurie Askenatzis  1 , Joëlle Bigay  2 , Bruno Antonny  2 , Hélène Levaique  1 , Emilie Mérour  1 , Jérôme Bignon  1 , Bruno Mesmin  2 , Sandy Desrat  1 , Fanny Roussi  1
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Elaboration and profiling of the first OSBP degrader issued from natural Schweinfurthins

Carole Guimard et al. Bioorg Chem. 2025 Sep.

Abstract

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.

Keywords: Cholesterol homeostasis; Natural compounds; OSBP; PROTAC; Schweinfurthins; Triple negative cancer cells.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Fanny Roussi reports financial support was provided by Agence Nationale de la Recherche. Fanny Roussi reports financial support was provided by GEFLUC PARIS IDF. Carole Guimard reports financial support was provided by Paris-Saclay University. Gwenaelle Jezequel reports was provided by Paris-Saclay University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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