卵巢癌通常在初始诊断时的晚期被检测到。由于其无症状性质,早期诊断困难,发现5年生存率不到30%。与该疾病的发病机制相关的潜在分子事件尚未完全阐明。因此,预后生物标志物的鉴定以及开发靶向这些标志物的新型治疗剂变得相关.在这里,我们确定了四个卵巢癌数据集(GSE14407,GSE18520,GSE26712,GSE54388)中常见的264个差异表达基因(DEGs),分别。我们与过表达的基因(72个基因)构建了蛋白质-蛋白质相互作用(PPI)相互作用网络,并进行了基因富集分析。在PPI网络中,三种蛋白质;TTK蛋白激酶(TTK),NIMA相关激酶2(NEK2),和细胞周期蛋白依赖性激酶(CDK1)具有更高的节点度被进一步评估为我们的新型多靶标小分子NSC777201的治疗靶标。我们发现上调的DEGs在KEGG和与卵巢癌进展相关的基因本体中富集,女性配子协会,耳囊泡发育,染色体分离的调节,和治疗失败。除了PPI网络,独创性途径分析也牵涉到TTK,NEK2和CDK1在卵巢癌中升高的补救嘧啶和吡哆醛途径中的作用。TTK,NEK2和CDK1过表达,表现出高频率的遗传改变,并且与卵巢癌队列的不良预后相关。有趣的是,NSC777201对卵巢癌细胞系的NCI面板表现出抗增殖和细胞毒性活性(GI50=1.6µM〜1.82µM和TGI50=3.5µM〜3.63µM),并表现出强大的相互作用,对TTK具有更强的亲和力,NEK2和CDK1,比标准药物,紫杉醇。NSC777201显示了药物样候选物的理想特性,因此可以被认为是治疗卵巢癌的新型小分子。
Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease\'s pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.