Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

Marko Cigler; Hana Imrichova; Fabian Frommelt; Lucie Caramelle; Andrea Rukavina; Chrysanthi Kagiou; J Thomas Hannich; Cristina Mayor-Ruiz; Giulio Superti-Furga; Sonja Sievers; Alison Forrester; Luca Laraia; Herbert Waldmann; Georg E Winter

doi:10.1038/s41589-024-01614-4

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

Marko Cigler
, Hana Imrichova
, Fabian Frommelt
, Lucie Caramelle
, Andrea Rukavina
, Chrysanthi Kagiou
, J Thomas Hannich
, Cristina Mayor-Ruiz
, Giulio Superti-Furga
, Sonja Sievers
, Alison Forrester
, Luca Laraia
, Herbert Waldmann
, Georg E Winter

Research output: Contribution to journal › Article › peer-review

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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 antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR–Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum–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. (Figure presented.).

Original language	English
Article number	30693
Pages (from-to)	193-202
Number of pages	10
Journal	Nature Chemical Biology
Volume	21
Issue number	2
DOIs	https://doi.org/10.1038/s41589-024-01614-4
Publication status	Published - 21 Jun 2024

Funding

We are grateful to all the members of the laboratory of G.E.W., in particular N. Scholes, A. Hanzl and V. Brennsteiner, for helpful discussions and editorial contributions. We thank A. Koren, S. Kubicek and the CeMM Molecular Discovery Platform for their assistance with the profiling of the withanolide-inspired compound collection and the CeMM Biomedical Sequencing Facility for next-generation sequencing sample processing, sequencing and data curation. We thank the Morph-Im platform and staff at UNamur for their microscopy support. We moreover thank J. Zuber at the Research Institute of Molecular Pathology for sharing iCas9 cell lines and plasmids. CeMM and the laboratories of G.E.W. and G.S.-F. are supported by the Austrian Academy of Sciences. The laboratory of G.E.W. is further supported by funding from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement 851478). The laboratory of L.L. was supported by funding from the Novo Nordisk Foundation (NNF21OC0067188) and the Independent Research Fund Denmark (9041-00248B). A.F. is an FRS-FNRS Chercheur Qualifi\u00E9e. This research was funded in whole or in part by the Austrian Science Fund (FW; P32125, P31690 and P7909). For open access purposes, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. G.E.W. and G.S.-F. are scientific founders and shareholders of Proxygen and Solgate. G.E.W. is on the Scientific Advisory Board of Nexo Therapeutics. The laboratories of G.E.W. and G.S.-F. received research funding from Pfizer. C.M.-R. is part of the Scientific Advisory Board of Nostrum Biodiscovery. The C.M.-R. lab receives research funding from Aelin Therapeutics and Almirall. The remaining authors declare no competing interests.

Funders	Funder number
Austrian Science Fund
Aelin Therapeutics and Almirall
Österreichische Akademie der Wissenschaften
European Research Council
Pfizer
Novo Nordisk Fonden	NNF21OC0067188
Fundación Williams	P31690, P7909, P32125
Independent Research Fund Denmark	9041-00248B
Horizon 2020 Framework Programme	851478

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s41589-024-01614-4

s41589-024-01614-4Final published version, 17.1 MBLicence: CC BY

Cite this

Cigler, M., Imrichova, H., Frommelt, F., Caramelle, L., Rukavina, A., Kagiou, C., Hannich, J. T., Mayor-Ruiz, C., Superti-Furga, G., Sievers, S., Forrester, A., Laraia, L., Waldmann, H., & Winter, G. E. (2024). Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP. Nature Chemical Biology, 21(2), 193-202. Article 30693. https://doi.org/10.1038/s41589-024-01614-4

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title = "Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting 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 antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR–Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum–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. (Figure presented.).",

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Cigler, M, Imrichova, H, Frommelt, F, Caramelle, L, Rukavina, A, Kagiou, C, Hannich, JT, Mayor-Ruiz, C, Superti-Furga, G, Sievers, S, Forrester, A, Laraia, L, Waldmann, H & Winter, GE 2024, 'Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP', Nature Chemical Biology, vol. 21, no. 2, 30693, pp. 193-202. https://doi.org/10.1038/s41589-024-01614-4

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T1 - Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

AU - Cigler, Marko

AU - Imrichova, Hana

AU - Frommelt, Fabian

AU - Caramelle, Lucie

AU - Rukavina, Andrea

AU - Kagiou, Chrysanthi

AU - Hannich, J Thomas

AU - Mayor-Ruiz, Cristina

AU - Superti-Furga, Giulio

AU - Sievers, Sonja

AU - Forrester, Alison

AU - Laraia, Luca

AU - Waldmann, Herbert

AU - Winter, Georg E

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AB - 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 antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR–Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum–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. (Figure presented.).

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Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

Abstract

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Light Microscopy

Morphology - Imaging

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Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Equipment

Light Microscopy

Morphology - Imaging

Cite this