2. Academic Validation
  3. Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

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

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. herbert.waldmann@mpi-dortmund.mpg.de.
  • 8 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@cemm.oeaw.ac.at.
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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