Department of Cell Biology, Johns Hopkins University, Baltimore, Maryland 21205 United States.
Johns Hopkins Drug Discovery and Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205 United States.
ACS Chem Biol. 2024 Aug 16;19(8):1695-1704. doi: 10.1021/acschembio.4c00354. Epub 2024 Aug 6.
Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of lipid homeostasis and are essential for lipid metabolic reprogramming that supports tumor growth in multiple cancers. SREBP pathway inhibitors have been identified, but bioavailable compounds are lacking. To address this need, we designed a novel approach for screening a collection of 4,474 FDA-approved drugs. SREBPs are conditionally essential and required under low lipid conditions. Leveraging this property, we screened for drugs that inhibited pancreatic cancer cell growth in lipid-poor, but not lipid-rich, medium. The primary screen identified 83 drugs that inhibited cell growth in a lipid-dependent manner. Secondary assays examining SREBP target gene expression, SREBP proteolytic cleavage, and effects on human breast cancer cells identified 13 FDA-approved drugs that inhibit SREBP pathway activation. Taken together, we demonstrated that our screening approach can identify SREBP inhibitors from a small library of compounds. This high-throughput screening platform enables screening of large compound collections to discover novel small molecule SREBP inhibitors.
固醇调节元件结合蛋白（SREBP）转录因子是脂质稳态的核心调节剂，对于支持多种癌症中肿瘤生长的脂质代谢重编程至关重要。已经鉴定出 SREBP 途径抑制剂，但缺乏生物可利用的化合物。为了解决这一需求，我们设计了一种筛选 4474 种 FDA 批准药物的新方法。SREBPs 在低脂质条件下是条件必需的。利用这一特性，我们筛选了在脂质贫乏而非富含脂质的培养基中抑制胰腺癌细胞生长的药物。初步筛选发现了 83 种以脂质依赖方式抑制细胞生长的药物。进一步检测 SREBP 靶基因表达、SREBP 蛋白水解切割以及对人乳腺癌细胞的影响，确定了 13 种抑制 SREBP 途径激活的 FDA 批准药物。总之，我们证明了我们的筛选方法可以从一小部分化合物库中鉴定出 SREBP 抑制剂。这种高通量筛选平台能够筛选大型化合物库，以发现新型小分子 SREBP 抑制剂。
