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

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

PROVIDER: PRJNA941873 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23719917.fastq.gz	Fastqsanger.gz
	SRR23719918.fastq.gz	Fastqsanger.gz
	SRR23721136.fastq.gz	Fastqsanger.gz
	SRR23721137.fastq.gz	Fastqsanger.gz
	SRR23721138.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Project description: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.

2023-03-15 | GSE226849 | GEO

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

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. Here, we identify W7, 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 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, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound W7.

2023-03-15 | GSE226848 | GEO

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

2023-03-15 | GSE226847 | GEO

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

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.

2024-06-27 | PXD040692 | Pride

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.

2024-06-27 | PXD040694 | Pride

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

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

The response to lipopolysaccharide (LPS) of bone marrow derived macrophages treated with oxysterol binding protein (OSBP) inhibitors

Project description:The response to lipopolysaccharide (LPS) of bone marrow derived macrophages treated with oxysterol binding protein (OSBP) inhibitors

| PRJNA828534 | ENA

Structure-Activity Relationships of Ligand Binding to Oxysterol-Binding Protein (OSBP) and OSBP-Related Protein 4.

Project description:Oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4) have emerged as potentially druggable targets in antiviral and precision cancer drug development. Multiple structurally diverse small molecules function through targeting the OSBP/ORP family of proteins, including the antiviral steroidal compounds OSW-1 and T-00127-HEV2. Here, the structure-activity relationships of oxysterols and related compound binding to human OSBP and ORP4 are characterized. Oxysterols with hydroxylation at various side chain positions (i.e., C-20, C-24, C-25, and C-27)─but not C-22─confer high affinity interactions with OSBP and ORP4. A library of 20(S)-hydroxycholesterol analogues with varying sterol side chains reveal that side chain length modifications are not well tolerated for OSBP and ORP4 interactions. This side chain requirement is contradicted by the high affinity binding of T-00127-HEV2, a steroidal compound lacking the side chain. The binding results, in combination with docking studies using homology models of OSBP and ORP4, suggest multiple modes of steroidal ligand binding to OSBP and ORP4.

| S-EPMC10786236 | biostudies-literature

Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites

Project description:Abnormal distribution of cellular cholesterol is associated with numerous diseases, including cardiovascular and neurodegenerative diseases. Regulated transport of cholesterol is critical for maintaining its proper distribution in the cell, yet the underlying mechanisms remain unclear. Here, we show that lipid transfer proteins, namely ORP9, OSBP, and GRAMD1s/Asters (GRAMD1a/GRAMD1b/GRAMD1c), control non-vesicular cholesterol transport at points of contact between the ER and the trans-Golgi network (TGN), thereby maintaining cellular cholesterol distribution. ORP9 localizes to the TGN via interaction between its tandem α-helices and ORP10/ORP11. ORP9 extracts PI4P from the TGN to prevent its overaccumulation and suppresses OSBP-mediated PI4P-driven cholesterol transport to the Golgi. By contrast, GRAMD1s transport excess cholesterol from the Golgi to the ER, thereby preventing its build-up. Cells lacking ORP9 exhibit accumulation of cholesterol at the Golgi, which is further enhanced by additional depletion of GRAMD1s with major accumulation in the plasma membrane. This is accompanied by chronic activation of the SREBP-2 signalling pathway. Our findings reveal the importance of regulated lipid transport at ER-Golgi contacts for maintaining cellular cholesterol distribution and homeostasis.

2023-09-24 | GSE240960 | GEO

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