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.