一种共价化合物可选择性地抑制 RNA 去甲基化酶 ALKBH5,而不是 FTO

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Gan-Qiang Lai, Yali Li, Heping Zhu, Tao Zhang, Jing Gao, Hu Zhou and Cai-Guang Yang
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引用次数: 0

摘要

N6-甲基腺苷(m6A)是最常见的 mRNA 修饰,是真核生物基因调控所必需的。ALKBH5 是一种 m6A 去甲基化酶,是一个很有前景的靶点,尤其是在抗癌药物研发方面。然而,开发 ALKBH5 而非 FTO 的选择性强效抑制剂仍具有挑战性。在此,我们采用靶向共价抑制策略,发现了一种共价抑制剂 TD19,它能在基于蛋白质和肿瘤细胞的实验中选择性地抑制 ALKBH5 而不是 FTO 去甲基化酶。TD19 不可逆地修饰了 C100 和 C267 残基,阻止 ALKBH5 与含 m6A 的 RNA 结合。此外,TD19 在急性髓性白血病和多形性胶质母细胞瘤细胞系中显示出良好的抗癌功效。因此,与 FTO 相比,本研究开发的 ALKBH5 抑制剂可选择性地靶向 ALKBH5,有可能被用作研究 RNA 去甲基化酶生物学功能的探针和抗癌研究的先导化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO†

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO†

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO†

N 6-Methyladenosine (m6A) is the most prevalent mRNA modification and is required for gene regulation in eukaryotes. ALKBH5, an m6A demethylase, is a promising target, particularly for anticancer drug discovery. However, the development of selective and potent inhibitors of ALKBH5 rather than FTO remains challenging. Herein, we used a targeted covalent inhibition strategy and identified a covalent inhibitor, TD19, which selectively inhibits ALKBH5 compared with FTO demethylase in protein-based and tumor cell-based assays. TD19 irreversibly modifies the residues C100 and C267, preventing ALKBH5 from binding to m6A-containing RNA. Moreover, TD19 displays good anticancer efficacy in acute myeloid leukemia and glioblastoma multiforme cell lines. Thus, the ALKBH5 inhibitor developed in this study, which selectively targets ALKBH5 compared with FTO, can potentially be used as a probe for investigating the biological functions of RNA demethylase and as a lead compound in anticancer research.

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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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