2. Academic Validation
  3. Design and Structural Optimization of Orally Bioavailable RSK4 Inhibitors for the Treatment of Esophageal Squamous Cell Carcinoma

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

  • J Med Chem. 2026 Jan 8;69(1):368-386. doi: 10.1021/acs.jmedchem.5c02575.
Limin Leng 1,  Shuai He 2 3,  Manzhan Zhang 1,  Yanru Yang 2,  Yuanyuan Ge 1,  Yuan Yuan 1,  Qiqi Niu 1,  Xiayu Shi 1,  Zhuo Chen 1,  Zhenjiang Zhao 1,  Huan He 4,  Honglin Li 1 4,  Yufang Xu 1,  Zhe Wang 2,  Shiliang Li 1 4
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science and Technology, Shanghai 200030, China.
  • 2 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancer, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
  • 3 Department of Pathology, School of Basic Medicine and Forensic Science, Baotou Medical College, Baotou 014040, China.
  • 4 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China.
PMID: 41406994 DOI: 10.1021/acs.jmedchem.5c02575
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.

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