Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (<i>h</i>DHODH) Highlights Challenges in the Development of Fat Mass and Obesity-Associated Protein (FTO) Inhibitors.

ABSTRACT: FTO, an N ⁶-methyladenosine (m⁶A) and N ⁶,2'-O-dimethyladenosine (m⁶A_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 (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (hDHODH). Notably, structural similarities between the catalytic pockets of FTO and hDHODH enab

SUBMITTER: Tarullo M 

PROVIDER: S-EPMC11651170 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature