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

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-01 DOI:10.1016/j.ejmech.2025.117590

Chun Han , Chaohua Guo , Xumei Zheng , Lin Zhao , Miao Sun , Jian Li , Shijun Wang , Zhang Zhang , Zhijun Wang , Lintao Wu

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引用次数: 0

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.

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发现2,4-二苯胺嘧啶衍生物作为新型p90核糖体S6蛋白激酶（RSK）抑制剂

RSK或P90核糖体S6激酶在肿瘤细胞增殖和存活中起着至关重要的作用，使其成为癌症治疗的一个有吸引力的靶点。为了探索新的RSK抑制剂作为抗癌药物，设计并合成了一系列2,4-二胺嘧啶衍生物2b-2n和3a-3n。其中，化合物3e对RSK2表现出明显的激酶抑制活性（IC50 = 37.89±3.08 nM），对HeLa、MIA PaCa-2、U937、SW620、HT-29、AGS和两种EGFR突变细胞（IC50 = 0.189 ~ 0.572 μM）均有明显的抗增殖作用。此外，化合物3e对RSK具有高亲和力，可有效抑制HeLa细胞中的RSK活性。在G2/M期引起细胞凋亡和细胞周期阻滞。此外，3e在保持可接受的安全性的同时显示出相当大的体内抗癌活性。这些发现表明，化合物3e具有2,4-二苯胺嘧啶支架，可以作为一种有希望的癌症治疗RSK抑制剂。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.