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

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.

Twenty-nine synthetic flavonols were designed to inhibit ALK-5 and docked using Schrodinger's Glide XP. The compounds were synthesized via a green, one-pot method and characterized using ¹H-NMR, ¹³CNMR, Mass Spectrometry, CHN analysis, and IR spectroscopy. The anti-cancer activity was evaluated against MiAPaCa-2 pancreatic cancer cells by measuring GI50, TGI, and LC₅₀. ALK-5 inhibition was quantified using the ADP-Glo® Kinase Assay, assessing ATP transfer.

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 IC₅₀ of 14.92 ± 3.54 μM. Ten flavonols exhibited strong cytotoxicity (GI₅₀ < 10 μM), while four others showed moderate activity (GI₅₀ = 23-26 μM).

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.

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