Among the promising therapeutic targets for treating cancer are the continuously active STAT proteins, which are important in the progression of many malignancies. Here, we detail the STAT3/5 inhibitory action and thiopyrimidine/chalcone hybrid design, production, and anti-hepatocellular carcinoma activity. The prepared hybrids were assessed for their cytotoxic effect on HepG2 and Huh7 liver cancer cells. The most active compounds 5e and 5h (IC50 range from 0.55 to 2.58 μM) were further evaluated against normal THLE cells to examine their safety profiles. The hybrids 5e and 5h were additionally tested for their potential to inhibit STAT3 and STAT5a. They showed dual inhibitory action, with a decrease in the level of STAT3 by 65 and 87 times, respectively, and a decrease in the level of STAT5 by 60 and 79.5 times, respectively, compared to the control. Additionally, western blot analysis of compound 5h revealed inhibition of STAT3 and STAT5 phosphorylation at Tyr705 and Tyr694, respectively, with only a slight decrease in the total expression of STAT3 and STAT5 proteins. And lastly, molecular docking research provided additional insight on the 5h binding mechanism in the STAT3 and STAT5 SH2 domains.
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