State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2023 Dec 14;66(23):15944-15959. doi: 10.1021/acs.jmedchem.3c01374. Epub 2023 Nov 20.
MA (-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 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. increased the abundance of mA modifications in AML cells, reduced the mRNA stability of , and inhibited cell cycle progression. Furthermore, 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.
m6A（N6-甲基腺苷）在调控 RNA 加工、剪接、成核、翻译和稳定性方面发挥着重要作用。 AlkB 同源物 5（ALKBH5）是一种依赖 Fe(II)/2-氧戊二酸（2-OG）的双加氧酶，可使单甲基化或二甲基化的腺苷脱甲基化。ALKBH5 可被视为多种人类癌症的致癌因子。然而，发现有效且选择性的 ALKBH5 抑制剂仍然是一个挑战。我们通过基于结构的虚拟筛选和优化，发现 是一种新型且选择性的 ALKBH5 抑制剂。 不是 2-氧戊二酸类似物，可选择性抑制 ALKBH5 相对于 FTO 的脱甲基酶活性。 在 AML 细胞中增加了 m6A 修饰的丰度，降低了 的 mRNA 稳定性，并抑制了细胞周期进程。此外， 在 MV4-11 异种移植小鼠模型中显著抑制肿瘤生长，且具有良好的安全性。总之，我们的研究结果强调了开发选择性 ALKBH5 探针的重要性，这将为进一步研究 ALKBH5 靶向治疗铺平道路。
