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(8H)-one derivatives through metabolism prediction-guided drug design optimizing the lead compound 14f (F = 0.99%). Among them, compound 16o exhibited potent RSK4 inhibition (IC50 = 17 nM) and significantly improved oral bioavailability (F = 21.40%). It effectively suppressed ESCC cell growth and invasion in vitro, and inhibited phosphorylation of RSK4 downstream targets. In ESCC mouse models, oral administration of 16o (50 mg/kg) markedly inhibited tumor growth and metastasis. These results identify 16o as a promising, orally available RSK4 inhibitor deserving further development for ESCC therapy.