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.