2. Academic Validation
  3. Discovery of 2,4-dianilinopyrimidine derivatives as novel p90 ribosomal S6 protein kinase (RSK) inhibitors

Discovery of 2,4-dianilinopyrimidine derivatives as novel p90 ribosomal S6 protein kinase (RSK) inhibitors

  • Eur J Med Chem. 2025 Jul 5:291:117590. doi: 10.1016/j.ejmech.2025.117590.
Chun Han 1,  Chaohua Guo 2,  Xumei Zheng 2,  Lin Zhao 2,  Miao Sun 3,  Jian Li 1,  Shijun Wang 1,  Zhang Zhang 4,  Zhijun Wang 5,  Lintao Wu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China.
  • 2 Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China; School of Chemistry & Material Science, Shanxi Normal University, Taiyuan, 030006, China.
  • 3 College of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 4 College of Pharmacy, Jinan University, Guangzhou, 510632, China. Electronic address: zhang_zhang@jnu.edu.cn.
  • 5 Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China. Electronic address: czxywzj@czc.edu.cn.
  • 6 Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China. Electronic address: ltwu@live.cn.
PMID: 40199026 DOI: 10.1016/j.ejmech.2025.117590
Abstract

RSK, or p90 ribosomal S6 kinase, plays a crucial role in tumor cell proliferation and survival, making it an appealing target for Cancer therapies. With the aim to explore novel RSK inhibitors as Anticancer agents, a series of 2,4-dianilinopyrimidine derivatives 2b-2n and 3a-3n have been designed and synthesized. Among them, compound 3e displayed substantial kinase inhibitory activity against RSK2 (IC50 = 37.89 ± 3.08 nM) and a potent antiproliferative effect against a range of cell lines, including HeLa, MIA PaCa-2, U937, SW620, HT-29, AGS, and two kinds of EGFR mutant cells (IC50s = 0.189-0.572 μM). Additionally, compound 3e exhibited a high affinity for RSK and effectively inhibited RSK activity in HeLa cells. It triggered significant Apoptosis and caused cell cycle arrest in the G2/M phase. Moreover, 3e displayed considerable in vivo Anticancer activity while maintaining an acceptable safety profile. These findings imply that compound 3e, featuring a 2,4-dianilinopyrimidine scaffold, could serve as a promising RSK inhibitor for Cancer treatment.

Keywords

2,4-Dianilinopyrimidine; Anticancer; Kinase inhibitor; RSK; Targeted therapy.

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