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
  • 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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