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
  • 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: [email protected].
  • 5. Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China. Electronic address: [email protected].
  • 6. Key Laboratory of Antitumor Drugs and Companion Diagnostic Reagents, Department of Chemistry, Changzhi University, Changzhi, 046011, China. Electronic address: [email protected].
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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