Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

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 (2024). Nat Chem Biol.

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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