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image of Targeting TGF-βR1 Signaling Pathway in Pancreatic Cancer: A Potential Approach with Synthetic Flavanols

Abstract

Introduction

Pancreatic adenocarcinoma is a highly aggressive cancer with a poor prognosis and a five-year survival rate of just 13%. Its asymptomatic onset, rapid progression, and resistance to therapy make it challenging to treat. Transforming Growth Factor-β (TGF-β) signaling, particularly through TGF-β Receptor 1 (TGF-βR1/ALK-5), plays a major role in tumor progression by inducing Epithelial-Mesenchymal Transition (EMT), immune evasion, and apoptosis resistance. Targeting ALK-5 is a promising strategy for therapeutic intervention.

Methods

Twenty-nine synthetic flavonols were designed to inhibit ALK-5 and docked using Schrodinger’s Glide XP. The compounds were synthesized a green, one-pot method and characterized using 1H-NMR, 13C-NMR, Mass Spectrometry, CHN analysis, and IR spectroscopy. The anti-cancer activity was evaluated against MiAPaCa-2 pancreatic cancer cells by measuring GI, TGI, and LC. ALK-5 inhibition was quantified using the ADP-Glo® Kinase Assay, assessing ATP transfer.

Results

RFL-1 showed the strongest binding affinity (–9.38 kcal/mol) at ALK-5’s active site and the highest kinase inhibition (ATP transfer: 3.67%), outperforming quercetin (9.22%). It also demonstrated an IC of 14.92 ± 3.54 µM. Ten flavonols exhibited strong cytotoxicity (GI < 10 μM), while four others showed moderate activity (GI = 23-26 μM).

Discussion

RFL-1 and related flavonols (RFL-12, RFL-20, RFL-25, RFL-28) effectively inhibited ALK-5 and suppressed the growth of pancreatic cancer cells. Their dual activity supports further development as targeted anti-cancer agents.

Conclusion

Synthetic flavonols, particularly RFL-1, show promise as ALK-5 inhibitors and potential therapies for pancreatic adenocarcinoma, warranting further validation.

© 2025 Bentham Science Publishers
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2025-10-02
2025-12-24

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Targeting TGF-βR1 Signaling Pathway in Pancreatic Cancer: A Potential Approach with Synthetic Flavanols
Bentham Science Publishers ; https://doi.org/10.2174/0118715206388963250901091741
/content/journals/acamc/10.2174/0118715206388963250901091741
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  • Article Type:     Research Article
Keywords: pancreatic cancer ; transforming growth factor receptor 1 inhibitors/ ALK-5 inhibitors (activitin-like kinase-5) ; ADP-Glo™ kinase assay ; Flavonols ; molecular docking using Glide software

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