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Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein
Journal article   Peer reviewed

Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein

Laura Depta, Nianzhe He, Maria Lillevang Madsen, Matilde Lind Hartvig Nielsen, Hogan P. Bryce-Rogers, Samantha C. Waterworth, Jeffrey D. Neighbors, David P. Stockdale, Michael P. Callahan, Nolan R. Mente, …
RSC medicinal chemistry, Vol.16(12), pp.6262-6274
12/01/2025
DOI: 10.1039/D5MD00625B
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC12635928/View
Open Access

Abstract

Schweinfurthins (SWs) are natural products isolated from the plant genus Macaranga which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar activities. Their known target is the sterol transport protein (STP) oxysterol-binding protein (OSBP), a key mediator and regulator of lipid transport between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). However, until now the underlying structure-activity relationships (SAR), as well as the cellular toxicity-target engagement relationships of SWs towards OSBP have not been well-studied. In this study, we present the first comprehensive SAR and selectivity study by characterizing 59 SW analogues utilizing our STP screening panel. Complementing detailed docking studies shine light into the SW-OSBP interactions and unravel amino acid residues critical for potent binding to OSBP. Additionally, we demonstrate cellular target engagement and correlate cancer cell cytotoxicity with Golgi fragmentation as a phenotypic consequence of OSBP inhibition by selected SW analogues. Therefore, this study will pave the way for more focused investigations and therapeutic applications of OSBP inhibitors.

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