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

Yuan Yuan; Junpeng Xu; Lei Jiang; Kangjie Yu; Yuanyuan Ge; Mingyang Li; Huan He; Qiqi Niu; Xiayu Shi; Linni Fan; Zhuo Chen; Zhenjiang Zhao; Shiliang Li; Yufang Xu; Zhe Wang; Honglin Li

doi:10.1021/acs.jmedchem.1c00969

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

J Med Chem. 2021 Sep 23;64(18):13572-13587. doi: 10.1021/acs.jmedchem.1c00969. Epub 2021 Sep 9.

Authors

Yuan Yuan¹, Junpeng Xu², Lei Jiang¹, Kangjie Yu², Yuanyuan Ge¹, Mingyang Li², Huan He¹, Qiqi Niu¹, Xiayu Shi¹, Linni Fan², Zhuo Chen¹, Zhenjiang Zhao¹, Shiliang Li¹, Yufang Xu¹, Zhe Wang², Honglin Li^{1

3}

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
² State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
³ Research and Development Department, Jiangzhong Pharmaceutical Co., Ltd., Nanchang 330096, China.

PMID: 34496560
DOI: 10.1021/acs.jmedchem.1c00969

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Esophageal Neoplasms / drug therapy*
Esophageal Squamous Cell Carcinoma / drug therapy*
Humans
Male
Mice
Mice, Nude
Molecular Docking Simulation
Molecular Structure
Oxazines / chemical synthesis
Oxazines / metabolism
Oxazines / pharmacokinetics
Oxazines / therapeutic use*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use*
Rats
Rats, Sprague-Dawley
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 90-kDa / chemistry
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Oxazines
Protein Kinase Inhibitors
Pyrimidines
RPS6KA6 protein, human
Ribosomal Protein S6 Kinases, 90-kDa