Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

  • Nat Chem Biol. 2024 Jun 21. doi: 10.1038/s41589-024-01614-4.
Marko Cigler  1 ,  Hana Imrichova  1 ,  Fabian Frommelt  1 ,  Lucie Caramelle  2 ,  Laura Depta  3 ,  Andrea Rukavina  1 ,  Chrysanthi Kagiou  1 ,  J Thomas Hannich  1 ,  Cristina Mayor-Ruiz  1  4 ,  Giulio Superti-Furga  1  5 ,  Sonja Sievers  6 ,  Alison Forrester  2 ,  Luca Laraia  3 ,  Herbert Waldmann  7 ,  Georg E Winter  8
Affiliations
  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2. Unit of Research of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium.
  • 3. Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
  • 4. IRB Barcelona-Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 5. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 6. Department of Chemical Biology, Max-Planck Institute of Molecular Physiology, Dortmund, Germany.
  • 7. Department of Chemical Biology, Max-Planck Institute of Molecular Physiology, Dortmund, Germany. [email protected].
  • 8. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected].
PMID: 38907113 DOI: 10.1038/s41589-024-01614-4
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.

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