Discovery of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML
Yingzhe Wang, Hongyu Li, Yan Zhang, Ruixin Jiang, Jun Xu, Jing Gu, Zheng Jiang, Zheng Jiang, Zhengyu Jiang, Zhengyu Jiang, Qidong You, Xiaoke Guo
Abstract
M 6 A ( N 6 -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 m 6 A 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.