表型药物发现(PDD)是一种有效的药物发现方法,通过观察对疾病表型的治疗效果,特别是在复杂的疾病系统中。三阴性乳腺癌(TNBC)由几种复杂的疾病特征组成,包括高度的肿瘤异质性,高侵袭和转移潜能,缺乏有效的治疗靶点。因此,通过PDD识别有效和新颖的药物是TNBC药物开发的当前趋势。在这项研究中,使用4-(苯基磺酰基)吗啉作为药效团合成了23个新的小分子。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(0.90μM)。为了研究GL24的肿瘤抑制机制,使用转录组学分析来检测GL24治疗后基因表达的扰动。其次是基因本体论(GO)分析,基因集富集分析(GSEA),和京都基因和基因组百科全书(KEGG)分析,多个ER应激依赖性肿瘤抑制信号被识别,如未折叠蛋白反应(UPR),p53通路,G2/M检查点,和E2F目标。由GL24触发的大多数确定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的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。
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.