Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity

Fat mass obesity-associated protein
(FTO) has been emerging
as
a potential therapeutic target for drug discovery in RNA epigenetics.
In this work, a series of novel FTO inhibitors featuring an acylhydrazone
scaffold were identified, and the optimized compounds 8t–v showed potent FTO inhibitory activities with
IC50 values ranging from 7.1 to 9.4 μM. FTO inhibitor 8t, as the lead compound, exhibited potent antiproliferative
capacities against MOLM13, NB4, and THP-1 with IC50 values
of 0.35, 0.59, and 0.70 μM, respectively, and remarkably induced
NB4 cell apoptosis. Compound 8t also inhibited the FTO
demethylation, enhanced the abundance of m6A, stabilized
FTO protein folding, and regulated the oncogenic FTO signaling pathway.
Importantly, compound 8t significantly caused a tumor
volume reduction and tumor weight loss with a tumor growth inhibition
(TGI) value of 51% in NB4 xenograft mice. Overall, our work provided
valuable lead compounds for FTO inhibitors featuring an acylhydrazone
scaffold with potent antileukemia activity both in vitro and in vivo.

脂肪量与肥胖相关蛋白（Fat mass obesity-associated protein, FTO）已逐渐成为RNA表观遗传学领域药物研发的潜在治疗靶点。本研究中，我们鉴定出一系列以酰腙为骨架的新型FTO抑制剂，优化得到的化合物8t~v展现出强效的FTO抑制活性，其半最大抑制浓度（IC50）范围为7.1至9.4 μM。作为先导化合物的FTO抑制剂8t，对MOLM13、NB4及THP-1细胞均展现出强效抗增殖活性，对应的IC50值分别为0.35、0.59和0.70 μM，且可显著诱导NB4细胞凋亡。化合物8t还可抑制FTO的去甲基化活性，提升N6-甲基腺嘌呤（m6A）的修饰水平，稳定FTO蛋白的折叠构象，并调控致癌性FTO信号通路。尤为重要的是，在NB4细胞异种移植瘤小鼠模型中，化合物8t可显著缩小肿瘤体积、减轻肿瘤重量，其肿瘤生长抑制率（TGI）达51%。综上，本研究为基于酰腙骨架的FTO抑制剂提供了极具价值的先导化合物，这类抑制剂在体外及体内均展现出强效的抗白血病活性。