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In silico approach and mass spectrometry-based proteome profiling unravel IGF-1R inhibition potential of 3-(2-furoyl)-indole scaffolds in hepatocellular carcinoma

ABSTRACT: Considering the multi-targeting potential of furan-indole hybrids as anticancer agents, this study aimed to unveil the mechanism of new 3-(2-furoyl)-indole derivatives for their cytotoxicy on hepatocellular carcinoma cells. Initially, we conducted an in vitro cytotoxicity assay for thirteen 3-(2-furoyl)-indole derivatives on HepG2 and MCF-7 cells using MTT assay, correlating the results with in silico screening of the selected drug targets. Among them, compounds 4a, 4b, and 4c demonstrated better selectivity towards HepG2 cells than MCF-7 cells. This was in good agreement with docking studies, which showed the high binding affinity of compound 4a to the Chain A of IGF-1R at Ile1160, Glu 1080, Met 1082 and Asp-1086, similar to reference ligand. Molecular dynamic study inferred the stable and high binding affinity of compound 4a to IGF-1R. The RMSD and RMSF values were found to be acceptable, and accordingly, a pharmacophore model was constructed. Hence, we conducted label-free quantitative proteome profiling of HepG2 cells treated with active compounds using an in-solution trypsin digestion procedure followed by high-resolution mass spectrometric analysis. We noticed that compound 4a targets IGF-1R pathway by dysregulation of proteins such as SHC-transforming protein 1(P29353), Mitogen-activated protein kinase kinase 3 isoform B variant (Q53EZ9), dual specificity mitogen-activated protein kinase kinase 4 (P45985), stress-activated protein kinase JNK (A0A286YF97), and mitogen-activated protein kinase (E9PQW4). In addition, the apoptotic activities of 4a, 4b, and 4c were studied against HepG2 cells using FACS. These findings are in good agreement with our in silico results, proteome profiling, and also earlier reports on indole compounds. Furthermore, we predicted the in silico ADMET property of the compounds.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: RAMALINGAM PERAMAN

LAB HEAD: Dr. P. Ramalingam

PROVIDER: PXD054680 | Pride | 2026-03-09

REPOSITORIES: Pride

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

Myrsing Efficiency E Mouli H M Chandra HMC Nikhil Pallaprolu P Deepali Sahu Abhishek A Jana Anupam A Ramalingam P P

Future medicinal chemistry 20250303 5

<h4>Aim</h4>This study investigates the anti-proliferative potential and possible molecular mechanisms of 3-(2-furoyl)-indole derivatives against HepG2.<h4>Method</h4>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.<h4>Results</h4>Lead compound 4a, showed IC50 of 27 µM agai ...[more]

PMID: 40028717

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