PXD040694

PXD040694 is an original dataset announced via ProteomeXchange.

Title	Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP (Expression proteomics)
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.
HostingRepository	PRIDE
AnnounceDate	2024-06-27
AnnouncementXML	Submission_2024-06-27_05:52:20.591.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD040694
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Fabian Frommelt
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-08 13:47:31	ID requested
⏵ 1	2024-06-27 05:52:21	announced

10.1038/s41589-024-01614-4;

10.6019/PXD040694;

Cigler M, Imrichova H, Frommelt F, Caramelle L, Depta L, Rukavina A, Kagiou C, Hannich JT, Mayor-Ruiz C, Superti-Furga G, Sievers S, Forrester A, Laraia L, Waldmann H, Winter GE, Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP. Nat Chem Biol, ():(2024) [pubmed]

submitter keyword: thermal proteome profiling, expression proteomics, withanolides,natural product-inspired compound libraries

Dr Georg E. Winter
contact affiliation	Winter Lab, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
contact email	gwinter@cemm.oeaw.ac.at
lab head
Fabian Frommelt
contact affiliation	CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
contact email	fabian.frommelt@hotmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040694
     1. Label: PRIDE project
     2. Name: Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP (Expression proteomics)