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.