TY - JOUR
T1 - Design and Structural Optimization of Orally Bioavailable RSK4 Inhibitors for the Treatment of Esophageal Squamous Cell Carcinoma
AU - Leng, Limin
AU - He, Shuai
AU - Zhang, Manzhan
AU - Yang, Yanru
AU - Ge, Yuanyuan
AU - Yuan, Yuan
AU - Niu, Qiqi
AU - Shi, Xiayu
AU - Chen, Zhuo
AU - Zhao, Zhenjiang
AU - He, Huan
AU - Li, Honglin
AU - Xu, Yufang
AU - Wang, Zhe
AU - Li, Shiliang
N1 - Publisher Copyright:
© 2025 American Chemical Society
PY - 2026/1/8
Y1 - 2026/1/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105026789430
U2 - 10.1021/acs.jmedchem.5c02575
DO - 10.1021/acs.jmedchem.5c02575
M3 - 文章
C2 - 41406994
AN - SCOPUS:105026789430
SN - 0022-2623
VL - 69
SP - 368
EP - 386
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -