虽然胆固醇代谢是抗肿瘤药物开发的共同途径,没有具体的靶点和临床用药。这里,基于我们先前对固醇O-酰基转移酶1(SOAT1)在肝细胞癌中的研究,我们试图筛选一种有效的靶向药物来精确治疗肝细胞癌,从胆固醇代谢的角度来看,阐明胆固醇调节与肿瘤发生发展的关系。
在这项研究中,我们开发了一种用于靶蛋白药物筛选的虚拟筛选集成亲和筛选技术。一系列体外和体内实验用于药物活性验证。通过多组学分析和流式细胞术分析来探讨抗肿瘤机制。蛋白质组和转录组的比较分析结合患者的生存随访信息揭示了筛选药物的临床治疗潜力。
我们筛选了三种化合物,尼洛替尼,ABT-737和evacetrapib,表现出与SOAT1的最佳结合。特别是,尼洛替尼显示出对SOAT1蛋白的高亲和力,并在体外和体内显着抑制肿瘤活性。多组学分析和流式细胞术分析表明,SOAT1靶向化合物可重新编程肿瘤中的胆固醇代谢,并增强CD8T细胞和嗜中性粒细胞以抑制肿瘤生长。
合照,我们报道了几种高亲和力SOAT1配体,并证明了它们在肝癌精准治疗中的临床潜力,并揭示了SOAT1靶向化合物的潜在抗肿瘤机制。
Although cholesterol metabolism is a common pathway for the development of antitumor drugs, there are no specific targets and drugs for clinical use. Here, based on our previous study of sterol O-acyltransferase 1 (
SOAT1) in hepatocelluar carcinoma, we sought to screen an effective targeted drug for precise treatment of hepatocelluar carcinoma and, from the perspective of cholesterol metabolism, clarify the relationship between cholesterol regulation and tumorigenesis and development.
In this study, we developed a virtual screening integrated affinity screening technology for target protein drug screening. A series of in vitro and in vivo experiments were used for drug activity verification. Multi-omics analysis and flow cytometry analysis were used to explore antitumor mechanisms. Comparative analysis of proteome and transcriptome combined with survival follow-up information of patients reveals the clinical therapeutic potential of screened drugs.
We screened three compounds, nilotinib, ABT-737, and evacetrapib, that exhibited optimal binding with
SOAT1. In particular, nilotinib displayed a high affinity for
SOAT1 protein and significantly inhibited tumor activity both in vitro and in vivo. Multi-omics analysis and flow cytometry analysis indicated that
SOAT1-targeting compounds reprogrammed the cholesterol metabolism in tumors and enhanced CD8+ T cells and neutrophils to suppress tumor growth.
Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of
SOAT1-targeting compounds.