Discovery, Optimization, and Structure–Activity Relationship Study of Novel and Potent RSK4 Inhibitors as Promising Agents for the Treatment of Esophageal Squamous Cell Carcinoma

Ribosomal
S6 protein kinase 4 (RSK4) was identified to be a promising
target for the treatment of esophageal squamous cell carcinoma (ESCC)
in our previous research, whose current treatments are primarily chemotherapy
and radiotherapy due to the lack of targeted therapy. However, few
potent and specific RSK4 inhibitors are reported. In this study, a
series of 1,4-dihydro-2H-pyrimido­[4,5-d]­[1,3]­oxazin-2-ones derivatives were designed and synthesized as
novel and potent RSK4 inhibitors. Compound 14f was identified
with potent RSK4 inhibitory activity both in vitro and in vivo. 14f significantly inhibited
the proliferation and invasion of ESCC cells in vitro with IC50 values of 0.57 and 0.98 μM, respectively.
It dose dependently inhibited the phosphorylation of RSK4 downstream
substrates while exerting little effect on the substrates of RSK1-3
in ESCC cells. The markedly suppressed tumor growth and no observed
toxicity to main organs in the ESCC xenograft mouse model suggested 14f to be a promising RSK4-targeting agent for ESCC treatment.