posted on 2023-11-20, 20:05authored byYing-Zhe Wang, Hong-Yu Li, Yan Zhang, Rui-Xin Jiang, Jun Xu, Jing Gu, Zheng Jiang, Zheng-Yu Jiang, Qi-Dong You, Xiao-Ke Guo
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.