Preclinical evaluation demonstrates potent antitumor activity of oral RSK4 inhibitor 16o in esophageal squamous cell carcinoma models, highlighting a viable targeted therapeutic strategy.
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 H )-one derivatives through metabolism prediction-guided drug design optimizing the lead compound 14f ( F = 0.99%). Among them, compound 16o exhibited potent RSK4 inhibition (IC 50 = 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.
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Leng et al. (2025) studied this question.
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