Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.

中文翻译：

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4-(苯磺酰基)吗啉衍生物诱导的多途径调控对三阴性乳腺癌的作用


表型药物发现（PDD）是通过观察对疾病表型的治疗效果，特别是在复杂疾病系统中的治疗效果而有效的药物发现方法。三阴性乳腺癌（TNBC）具有多种复杂的疾病特征，包括肿瘤异质性高、侵袭性和转移性高以及缺乏有效的治疗靶点。因此，通过PDD寻找有效的新型药物是当前TNBC药物开发的趋势。在这项研究中，使用 4-(苯磺酰基)吗啉作为药效团合成了 23 种新型小分子。在这些衍生物中，GL24 ( 4m ) 在 MDA-MB-231 细胞中表现出最低的半最大抑制浓度值 (0.90 µM)。为了研究 GL24 的肿瘤抑制机制，使用转录组分析来检测 GL24 治疗后基因表达的扰动。随后通过基因本体（GO）分析、基因集富集分析（GSEA）和京都基因与基因组百科全书（KEGG）分析，鉴定出多种内质网应激依赖性肿瘤抑制信号，如未折叠蛋白反应（UPR）、p53途径、G2/M 检查点和 E2F 目标。大多数已确定的由 GL24 触发的途径最终导致细胞周期停滞，然后导致细胞凋亡。总之，我们开发了一种新型 4-(苯磺酰基)吗啉衍生物 GL24，具有通过 ER 应激依赖性肿瘤抑制信号抑制 TNBC 细胞生长的强大潜力。