Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity
Xuewu Liang, Yue Huang, Hairu Ren, Qi Liu, Liang Chen, Jiayan Zhao, Xiangqian Gao, Jian Lü, Cai‐Guang Yang, Hong Liu
Abstract
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 IC 50 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 IC 50 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 m 6 A, 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 .