Discovery of a novel RSK2 inhibitor for the treatment of metastatic pancreatic cancer.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chi-Hsiu Chung, Kai-Cheng Hsu, Ming-Min Huang, Huang-Ju Tu, Shiow-Lin Pan, Min-Wu Chao
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引用次数: 0

Abstract

Pancreatic cancer is among the most lethal malignancies, with a five-year survival rate of only 6%. For patients with metastatic disease, current treatments extend median survival by merely four months. This study addresses the urgent need for targeted therapies, as no specific drugs are currently available. Clinical analyses revealed significantly elevated RSK2 expression in pancreatic cancer tissues, associated with shorter survival. We aimed to identify a novel RSK2 inhibitor for metastatic pancreatic cancer. Through structure-based virtual screening, we identified NSYSU-115 as a promising candidate with an IC50 of 45.5 nM. At low concentrations, NSYSU-115 significantly suppressed colony formation, while higher concentrations reduced cell viability and proliferation. It also inhibited phosphorylation of IκBα, a known RSK2 substrate, in a dose- and time-dependent manner. Furthermore, NSYSU-115 impaired cell migration and altered epithelial-mesenchymal transition (EMT) markers. These findings highlight NSYSU-115 as a potent kinase inhibitor with promising therapeutic potential for pancreatic cancer treatment.

发现一种新的RSK2抑制剂用于治疗转移性胰腺癌。
胰腺癌是最致命的恶性肿瘤之一,5年生存率只有6%。对于转移性疾病患者,目前的治疗方法仅能延长中位生存期4个月。由于目前没有特异性药物可用,本研究解决了对靶向治疗的迫切需求。临床分析显示,胰腺癌组织中RSK2表达显著升高,与较短的生存期相关。我们旨在鉴定一种用于转移性胰腺癌的新型RSK2抑制剂。通过基于结构的虚拟筛选,我们确定NSYSU-115是一个有希望的候选分子,IC50为45.5 nM。在低浓度下,NSYSU-115显著抑制菌落形成,而高浓度则降低细胞活力和增殖。它还以剂量和时间依赖性的方式抑制已知RSK2底物IκBα的磷酸化。此外,NSYSU-115损害细胞迁移和改变上皮-间质转化(EMT)标记。这些发现突出了NSYSU-115作为一种有效的激酶抑制剂,在胰腺癌治疗中具有良好的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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