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Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP

ABSTRACT: Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules can provide a resource of invaluable chemotypes. Here, we identify orpinolide, a synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling and genome-scale CRISPR/Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate (PI4P) signaling at the endoplasmic reticulum (ER)-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of orpinolide. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound orpinolide.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226849 | GEO | 2023/03/15

REPOSITORIES: GEO

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [CRISPR screen]

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [RNA-Seq]

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP (TPP)

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP (Expression proteomics)

Project description:Metabolic alterations in cancers precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules can provide a resource of underexplored chemotypes. We identify W7, a synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling (including expression proteomics) and genome-scale CRISPR/Cas9 screens, we identify that W7 disrupts Golgi homeostasis via a mechanism that requires active PI4P signaling at the ER-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of W7. Collectively, our data reaffirms sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound W7.

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [RNA-Seq]

Project description:Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [RNA-Seq]

| PRJNA941879 | ENA

Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [CRISPR screen]

Project description:Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [CRISPR screen]

| PRJNA941878 | ENA

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| S-EPMC10786236 | biostudies-literature

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