Identification and Biological Evaluation of Juglone-Derived STAT3 Inhibitors against Colorectal Cancer

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) drives colorectal cancer progression by promoting cell proliferation, inhibiting apoptosis, and facilitating angiogenesis, making STAT3 a highly promising therapeutic target. In this study, a series of juglone-based quinone derivatives were designed, synthesized, and systematically evaluated as STAT3 inhibitors. Among them, compound YZZ-24 exhibited the strongest STAT3 binding affinity (K _i = 0.26 μM), which was significantly superior to juglone (K _i = 17.11 μM). Mechanistic studies revealed that YZZ-24 directly binds to STAT3 and effectively inhibits STAT3 phosphorylation at tyrosine 705 (p-STAT3^Tyr705) and STAT3 phosphorylation at serine 727 (p-STAT3^Ser727), thereby blocking downstream oncogenic signaling with minimal effects on upstream kinases. Cellular functional assays demonstrated that YZZ-24 exerts potent antitumor activity against colorectal cancer cells (IC₅₀ = 1.03 μM) and possesses an acceptable safety window (SI = 10.82). Collectively, YZZ-24 is a promising STAT3 inhibitor for the treatment of colorectal cancer.