TY - JOUR
T1 - Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein (OSBP)
AU - Depta, Laura
AU - He, Nianzhe
AU - Madsen, Maria Lillevang
AU - Nielsen, Matilde Lind Hartvig
AU - Bryce-Rogers, Hogan P.
AU - Waterworth, Samantha C.
AU - Neighbors, Jeffrey D.
AU - Stockdale, David P.
AU - Callahan, Michael P.
AU - Mente, Nolan R.
AU - Wiemer, David F.
AU - Beutler, John A.
AU - Laraia, Luca
N1 - Publisher Copyright:
This journal is © The Royal Society of Chemistry
PY - 2025/12/1
Y1 - 2025/12/1
N2 - 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 potency. 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. Complementary detailed docking studies shine light on 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.
AB - 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 potency. 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. Complementary detailed docking studies shine light on 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.
UR - https://www.scopus.com/pages/publications/105022252800
UR - https://www.scopus.com/pages/publications/105022252800#tab=citedBy
U2 - 10.1039/d5md00625b
DO - 10.1039/d5md00625b
M3 - Article
AN - SCOPUS:105022252800
SN - 2040-2503
VL - 16
SP - 6262
EP - 6274
JO - RSC Medicinal Chemistry
JF - RSC Medicinal Chemistry
IS - 12
ER -
