Targeting the RNA demethylase FTO for cancer therapy,RSC Chemical Biology

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Targeting the RNA demethylase FTO for cancer therapy
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-07-26 , DOI: 10.1039/d1cb00075f
Lin-Lin Zhou _{1,

2} , Hongjiao Xu _{1,

2} , Yue Huang _{1,

3} , Cai-Guang Yang _{1,

2,

3}

Affiliation

N ⁶ -Methyladenosine (m⁶A) is the most prevalent internal modification on mRNA and represents a new layer of gene expression in eukaryotes. The field of m⁶A-encoded epitranscriptomics was rejuvenated with the discovery of fat mass and obesity-associated protein (FTO) as the first m⁶A demethylase responsible for RNA modification in cells. Increasing evidence has revealed that FTO is significantly involved in physiological processes, and its dysregulation is implicated in various human diseases. Considering this functional significance, developing small-molecule modulators of the FTO protein represents a novel direction for biology research. However, such modulators remain in the early stages of development. Here, our review mainly focuses on the progress of FTO inhibitor development to date. We summarize screening methods used to identify FTO modulators, techniques used to assess the biological effects of these modulators, strategies used to achieve selective inhibition of FTO rather than its homologues, and the results of investigations of FTO modulator modes of action and anticancer efficacy. Thus, this review aims to facilitate novel chemical entity discovery, probe FTO biology, and promote the validation of FTO as a clinical drug target for cancer treatment.

中文翻译：

靶向 RNA 去甲基化酶 FTO 进行癌症治疗

N ⁶ -甲基腺苷 (m ⁶ A) 是 mRNA 最常见的内部修饰，代表真核生物中新的基因表达层。随着脂肪量和肥胖相关蛋白 (FTO) 作为第一个负责细胞 RNA 修饰的 m ⁶ A 去甲基化酶的发现，m ⁶ A 编码的表观转录组学领域重新焕发活力。越来越多的证据表明，FTO 显着参与生理过程，其失调与多种人类疾病有关。考虑到这种功能意义，开发 FTO 蛋白的小分子调节剂代表了生物学研究的一个新方向。然而，此类调节剂仍处于开发的早期阶段。在此，我们主要回顾迄今为止 FTO 抑制剂的开发进展。我们总结了用于鉴定 FTO 调节剂的筛选方法、用于评估这些调节剂的生物学效应的技术、用于实现 FTO 而不是其同系物的选择性抑制的策略，以及 FTO 调节剂作用模式和抗癌功效的研究结果。因此，本综述旨在促进新型化学实体的发现，探索 FTO 生物学，并促进 FTO 作为癌症治疗临床药物靶点的验证。

更新日期：2021-08-07

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