Therapeutic Targeting of Akt۱ in Oral Squamous Cell Carcinoma Using Natural Cinnamic Acids

Background: Akt۱, a serine/threonine kinase, plays a central role in cancer development and progression. Its overexpression correlates with aggressive phenotypes and poor prognosis in several types of cancers, such as oral squamous cell carcinoma (OSCC). Cinnamic acid derivatives (CADs) from natural sources exhibit anticancer properties, making them potential Akt۱ inhibitors. Methods: The binding affinities of ۱۹ CADs to the Akt۱ catalytic cleft were evaluated using molecular docking simulations and then compared with the Akt۱ inhibitor capivasertib. Interaction modes were analyzed to identify critical residues involved in ligand binding. Results: Cynarin demonstrated the highest binding affinity (ΔGbinding =-۱۳.۴۶ kcal/mol, Ki=۱۳۶.۴۸ pM), forming three hydrogen bonds with Akt۱. Rosmarinic acid with six hydrogen bonds also exhibited potent inhibition (ΔGbinding =-۱۱.۵۱ kcal/mol , Ki=۳.۶۷ nM). Both compounds represented superior binding compared to capivasertib. Conclusion: Cynarin and rosmarinic acid from natural sources showed promising inhibitory potential against Akt۱, suggesting their therapeutic values as anticancer agents targeting the PI۳K/Akt pathway in OSCC.