AlkB
脱甲基酶
化学
嘧啶
RNA剪接
癌症研究
生物化学
细胞生物学
核糖核酸
生物
基因
DNA修复
表观遗传学
作者
Yingzhe Wang,Hongyu Li,Yan Zhang,Ruixin Jiang,Jun Xu,Jing Gu,Zheng Jiang,Zhengyu Jiang,Qidong You,Xiaoke Guo
标识
DOI:10.1021/acs.jmedchem.3c01374
摘要
M6A (N6-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified DDO-2728 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. DDO-2728 was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. DDO-2728 increased the abundance of m6A modifications in AML cells, reduced the mRNA stability of TACC3, and inhibited cell cycle progression. Furthermore, DDO-2728 significantly suppressed tumor growth in the MV4–11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.
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