Nature Chemical Biology ( IF 12.9 ) Pub Date : 2024-06-21 , DOI: 10.1038/s41589-024-01614-4 Marko Cigler , Hana Imrichova , Fabian Frommelt , Lucie Caramelle , Laura Depta , Andrea Rukavina , Chrysanthi Kagiou , J. Thomas Hannich , Cristina Mayor-Ruiz , Giulio Superti-Furga , Sonja Sievers , Alison Forrester , Luca Laraia , Herbert Waldmann , Georg E. Winter
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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.
中文翻译:
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Orpinolide 通过抑制 OSBP 破坏白血病对胆固醇转运的依赖
癌症中的代谢改变会导致相关的依赖性,这些依赖性可以在治疗上利用。为了实现这一目标,天然产物启发的小分子可以提供宝贵的化学型资源。在这里,我们通过正交化学筛选鉴定了 orpinolide,一种合成的睡茄内酯类似物,具有显着的抗白血病特性。通过多组学分析和基因组规模的 CRISPR-Cas9 筛选,我们发现 orpinolide 通过一种需要内质网-高尔基膜界面处的活性磷脂酰肌醇 4-磷酸信号传导的机制来破坏高尔基体稳态。热蛋白质组分析和遗传验证研究表明,氧甾醇结合蛋白 OSBP 是 orpinolide 的直接且表型相关的靶标。总的来说,这些数据再次证实了甾醇转运作为白血病的一种治疗上可行的依赖性,并激发了随后通过探针样化合物奥皮诺内酯进行的转化研究。