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使用小分子抑制剂靶向癌细胞系中失调的分子途径作为一种有前景的治疗策略。

Targeting dysregulated molecular pathways in cancer cell lines using small molecule inhibitors as a promising therapeutic strategy.

作者信息

Almasoudi Hassan H, Khan Shoaib

机构信息

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.

Department of Chemistry, Abbottabad University of Science and Technology, Abbottabad, 22500, Pakistan.

出版信息

Sci Rep. 2025 Jul 7;15(1):24273. doi: 10.1038/s41598-025-06892-z.

Abstract

Biologically active heterocycles hold considerable potential in modulating cellular pathways associated with cancer progression. The present study focuses on the design and synthesis of novel thiadiazole-thiazolidinone hybrid scaffolds aimed at inhibiting the proliferation of cancer cells. The synthesized compounds were evaluated for their cytotoxic efficacy against human cancer cell lines, including HepG2 (hepatocellular carcinoma), MCF-7 (breast adenocarcinoma), HCT-116 (colorectal carcinoma), and W138 (lung fibroblast-derived carcinoma). Doxorubicin was used as a reference standard. Among the synthesized library, compound 7 demonstrated the most potent antiproliferative activity across all tested cell lines, indicating its potential role in targeting molecular pathways involved in tumor growth and survival. To elucidate the underlying mechanism of action, molecular docking studies were conducted to analyze ligand-target interactions at the atomic level, revealing favorable binding conformations within key regulatory proteins implicated in oncogenesis. Furthermore, enzyme kinetics and dose-response inhibition assays were performed to characterize the interaction dynamics and establish potential modes of inhibition. The ADMET profile of the lead compounds was also evaluated in silico, supporting their drug-likeness and safety for further preclinical development. These findings contribute valuable scaffolds for the development of new anticancer agents and highlight the importance of integrating chemical synthesis with molecular biology techniques in the discovery of targeted cancer therapeutics.

摘要

具有生物活性的杂环化合物在调节与癌症进展相关的细胞信号通路方面具有巨大潜力。本研究聚焦于新型噻二唑-噻唑烷酮杂合骨架的设计与合成,旨在抑制癌细胞的增殖。对合成的化合物针对包括HepG2(肝癌细胞)、MCF-7(乳腺腺癌细胞)、HCT-116(结肠癌细胞)和W138(肺成纤维细胞衍生癌细胞)在内的人类癌细胞系进行了细胞毒性评估。多柔比星用作参考标准。在合成的化合物库中,化合物7在所有测试细胞系中表现出最有效的抗增殖活性,表明其在靶向参与肿瘤生长和存活的分子信号通路中具有潜在作用。为阐明其潜在作用机制,进行了分子对接研究以在原子水平分析配体-靶点相互作用,揭示在肿瘤发生中涉及的关键调控蛋白内的有利结合构象。此外,进行了酶动力学和剂量反应抑制试验以表征相互作用动力学并确定潜在的抑制模式。还通过计算机模拟评估了先导化合物的ADMET特性,支持其类药性和安全性,以进行进一步的临床前开发。这些发现为新型抗癌药物的开发提供了有价值的骨架,并突出了在发现靶向癌症治疗药物中将化学合成与分子生物学技术相结合的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c6/12234987/44a7247a977a/41598_2025_6892_Fig1_HTML.jpg

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