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阻断致癌性帽依赖翻译作为非小细胞肺癌的治疗方法。

4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer.

机构信息

Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Wayzata High School, Plymouth, MN, USA.

出版信息

Invest New Drugs. 2021 Jun;39(3):636-643. doi: 10.1007/s10637-020-01036-8. Epub 2020 Nov 23.

Abstract

In order to suppress 5' cap-mediated translation a highly available inhibitor of the interaction between the 5' mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N-(p-chlorophenoxyethyl) guanosine 5'-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.

摘要

为了抑制 5' 帽介导的翻译,已经开发出一种高可用性的 5' mRNA 帽与 eIF4E 复合物相互作用抑制剂。4Ei-10 是 ProTide 类化合物的成员,具有较高的膜通透性,是 eIF4E 的强有效的化学拮抗剂。一旦被细胞摄取,它就会通过脂溶性 2-(甲硫基)乙基保护基团的连接子激活而被转化,然后 Hint1 P-N 键断裂为 N-(对氯苯氧基乙基)鸟苷 5'-单磷酸 (7-Cl-Ph-Ethyl-GMP)。利用这种强大的相互作用,已经证明 4Ei-10 抑制非小细胞肺癌 (NSCLC) 细胞的生长。此外,用 4Ei-10 处理 NSCLC 细胞会抑制翻译,并减少对维持恶性表型和抵抗细胞凋亡至关重要的一组细胞蛋白的表达,如 Bcl-2、survivin 和鸟氨酸脱羧酶 (ODC)。最后,由于靶向翻译抗凋亡蛋白,NSCLC 细胞对目前用于 NSCLC 治疗的现有抗肿瘤药物 gemcitabine 更加敏感。

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