Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (hDHODH) Highlights Challenges in the Development of Fat Mass and Obesity-Associated Protein (FTO) Inhibitors

Abstract

FTO, an N $^{6}$-methyladenosine (m$^{6}$A) and N $^{6}$,2'-O-dimethyladenosine (m$^{6}$A$_{m}$) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (D Show more