Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP.
Marko CiglerHana ImrichovaFabian FrommeltLucie CaramelleLaura DeptaAndrea RukavinaChrysanthi KagiouJ Thomas HannichCristina Mayor-RuizGiulio Superti-FurgaSonja SieversAlison ForresterLuca LaraiaHerbert WaldmannGeorg E WinterPublished in: Nature chemical biology (2024)
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.
Keyphrases
- endoplasmic reticulum
- genome wide
- crispr cas
- single cell
- binding protein
- acute myeloid leukemia
- dna methylation
- genome editing
- papillary thyroid
- high throughput
- copy number
- signaling pathway
- squamous cell
- living cells
- bone marrow
- electronic health record
- case control
- quantum dots
- young adults
- low density lipoprotein
- childhood cancer
- gene expression
- protein kinase
- fluorescent probe
- machine learning