Design and Structural Optimization of Orally Bioavailable RSK4 Inhibitors for the Treatment of Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with limited targeted treatment options. Ribosomal S6 protein kinase 4 (RSK4) is a potential therapeutic target, yet few potent and specific inhibitors have been reported. In this study, we designed and synthesized a series of pteridine-7(8<i>H</i>)-one derivatives through metabolism prediction-guided drug design optimizing the lead compound <b>14f</b> (<i>F</i> = 0.99%). Among them, compound <b>16o</b> exhibited potent RSK4 inhibition (IC₅₀ = 17 nM) and significantly improved oral bioavailability (<i>F</i> = 21.40%). It effectively suppressed ESCC cell growth and invasion <i>in vitro</i>, and inhibited phosphorylation of RSK4 downstream targets. In ESCC mouse models, oral administration of <b>16o</b> (50 mg/kg) markedly inhibited tumor growth and metastasis. These results identify <b>16o</b> as a promising, orally available RSK4 inhibitor deserving further development for ESCC therapy.