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Updated: Jan 8, 2026
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Design and Structural Optimization of Orally Bioavailable RSK4 Inhibitors for the Treatment of Esophageal Squamous
Limin Leng1, Shuai He2,3, Manzhan Zhang1
1School of Pharmacy, East China University of Science and Technology, Shanghai 200030, China.
Abstract:
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.
Insights
A novel drug candidate, 16o, shows promise for treating esophageal squamous cell carcinoma (ESCC). This potent Ribosomal S6 protein kinase 4 (RSK4) inhibitor demonstrates improved oral bioavailability and effectively inhibits ESCC growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with few targeted therapies.
- Ribosomal S6 protein kinase 4 (RSK4) is a potential therapeutic target in ESCC.
- Development of potent and specific RSK4 inhibitors is limited.
Purpose of the Study:
- To design and synthesize novel pteridine-7(8H)-one derivatives as RSK4 inhibitors.
- To identify an orally available compound with potent RSK4 inhibitory activity for ESCC treatment.
Main Methods:
- Metabolism prediction-guided drug design was employed to optimize a lead compound.
- A series of pteridine-7(8H)-one derivatives were synthesized and evaluated for RSK4 inhibition.
- In vitro assays assessed ESCC cell growth, invasion, and RSK4 downstream target phosphorylation.
- In vivo studies utilized ESCC mouse models to evaluate tumor growth and metastasis inhibition.
Main Results:
- Compound 16o demonstrated potent RSK4 inhibition with an IC50 of 17 nM.
- 16o exhibited significantly improved oral bioavailability (F = 21.40%).
- 16o suppressed ESCC cell growth and invasion in vitro and inhibited RSK4 phosphorylation.
- Oral administration of 16o markedly inhibited tumor growth and metastasis in ESCC mouse models.
Conclusions:
- Compound 16o is a promising, orally available RSK4 inhibitor.
- 16o shows significant potential for the treatment of esophageal squamous cell carcinoma.
- Further development of 16o for ESCC therapy is warranted.
