The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment , a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound showed the highest potency with IC values of 0.8 and 1.5 nM against Mnk1 and Mnk2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that effectively downregulated the downstream proteins -eIF4E, Mcl-1, and c-myc. Additionally, exhibited remarkable stability in rat plasma and rat and human microsomes. anti-tumor activity study suggested that treatment with suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of as a novel and potent Mnks inhibitor, which deserves further investigation.

中文翻译：

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Mnk1/2抑制剂4-(吲哚啉-1-基)-6-取代-吡啶并[3,2-d]嘧啶衍生物的设计、合成和生物学评价


Mnk-eIF4E 轴在肿瘤发展中起着至关重要的作用，抑制 Mnk 激酶是一种有前景的癌症治疗方法。从片段开始，设计并合成了一系列4-(二氢吲哚-1-基)-6-取代-吡啶并[3,2-]嘧啶衍生物。在这些衍生物中，化合物对 Mnk1 和 Mnk2 显示出最高的效力，IC 值分别为 0.8 和 1.5 nM。此外，它在 30 种选定的激酶中表现出良好的选择性。显着抑制 MOLM-13 和 K562 细胞系的生长并导致细胞周期停滞。此外，Western blot 检测显示，有效下调下游蛋白 -eIF4E、Mcl-1 和 c-myc。此外，在大鼠血浆以及大鼠和人类微粒体中表现出显着的稳定性。抗肿瘤活性研究表明，在 LL/2 同基因模型中，治疗可抑制肿瘤生长。这些发现凸显了 Mnks 作为新型有效抑制剂的潜力，值得进一步研究。