https://scholars.lib.ntu.edu.tw/handle/123456789/639711
標題: | Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer | 作者: | Yang, Fan-Wei TE-LUN MAI Lin, Ying-Chung Jimmy Chen, Yu-Chen Kuo, Shang-Che Lin, Chia-Ming Lee, Meng-Hsuan Su, Jung-Chen |
關鍵字: | 4-(phenylsulfonyl)morpholine derivatives; phenotypic drug discovery; transcriptomic analyses; triple negative breast cancer | 公開日期: | 5-二月-2024 | 出版社: | John Wiley & Sons, Inc | 卷: | Online Version of Record before inclusion in an issue | 起(迄)頁: | e2300435 | 來源出版物: | Archiv der Pharmazie | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/639711 | ISSN: | 0365-6233 1521-4184 |
DOI: | 10.1002/ardp.202300435 |
顯示於: | 生命科學系 |
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