Protein profiling uncovers IGF-1R inhibition potential of 3-(2-furoyl)-indole scaffolds in hepatocellular carcinoma.

IF 3.4 4区医学 Q3 CHEMISTRY, MEDICINAL Future medicinal chemistry Pub Date : 2025-03-01 Epub Date: 2025-03-03 DOI:10.1080/17568919.2025.2467616

Efficiency Myrsing, H M Chandra Mouli, Pallaprolu Nikhil, Deepali, Abhishek Sahu, Anupam Jana, P Ramalingam

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Abstract

Aim: This study investigates the anti-proliferative potential and possible molecular mechanisms of 3-(2-furoyl)-indole derivatives against HepG2.

Method: Identified hit compounds (4a, 4b, 4c) using MTT screening, were further investigated for their efficacy and mechanism of action through FACS studies, in-silico molecular docking, molecular dynamics (MD) simulations, and label-free quantitative proteome and ADMET prediction.

Results: Lead compound 4a, showed IC50 of 27 µM against HepG2 cells and a binding score of -8.077 kcal/mol against IGF-1 R (PDB ID: 5XFS) and formed a stable complex 100 ns. Proteomic study revealed significant downregulation of the IGF-1 R downstream signaling molecules and showed minimal toxicity and favorable drug-like properties.

Conclusion: These findings suggest that 4a is a promising IGF-1 R inhibitor and potential drug candidate against drug resistance hepatocellular carcinoma (HCC).

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蛋白谱揭示了3-（2-呋喃基）吲哚支架在肝细胞癌中抑制IGF-1R的潜力。

目的：研究3-（2-呋喃基）-吲哚衍生物对HepG2的抑制作用及其可能的分子机制。方法：通过MTT筛选筛选出命中化合物（4a, 4b, 4c），通过FACS研究、硅基分子对接、分子动力学（MD）模拟、无标记定量蛋白质组学和ADMET预测进一步研究其疗效和作用机制。结果：先导化合物4a对HepG2细胞的IC50为27µM，对IGF-1 R的结合评分为-8.077 kcal/mol (PDB ID: 5XFS)，形成稳定的配合物100 ns。蛋白质组学研究显示igf - 1r下游信号分子显著下调，显示出最小的毒性和有利的药物样特性。结论：4a是一种很有前景的igf - 1r抑制剂，也是抗耐药肝细胞癌的潜在候选药物。

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

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.