RNA epitranscriptomics represents a recently identified layer of regulation of genetic information. As the most abundant internal mRNA modification, m6A is critical for the regulation of mRNA metabolisms and impacts various biological and pathological processes.

The discovery of the fat-mass- and obesity-associated protein (FTO) as an m6A demethylase corroborates the m6A modification as a dynamic process. Recently, evidences prove that FTO is overexpressed in certain subtypes of apoptosis of human acute myeloid leukemia (AMLs) and promotes leukemogenesis. Thus, the development of effective inhibitors to target FTO's aberrant m6A demethylase activity is in urgent need for leukemia therapy.

To address this urgent issue, Prof. YANG Cai-guang’s group from the Shanghai Institute of Materia Medica of Chinese Academy of Sciences has identified a potential therapy for the acute myeloid leukemia by targeting the oncogenic RNA demethylase FTO through a joint study. The finding was published online in Cancer Cell.

Previously, Prof. Yang’s team had identified Meclofenamic Acid (MA) as a selective inhibitor of FTO demethylation over ALKBH5. However, the activity and selectivity of MA limited its uses in the study of biological functions of FTO demethylase.

After years of efforts, scientists developed successfully two selective FTO inhibitors through structure-based rational designs and chemical synthesis, namely FB23 and FB23-2, which efficiently reverse/suppress FTO-mediated aberrant epitranscriptome in AML cells.

In line with the regulation of FTO on downstream target genes, FB23 and FB23-2 treatment increased significantly the ASB2 and RARA while decreased the MYC and CEBPA abundance in an m6A modification-dependent manner in NB4 and MONOMAC6 cells.

Moreover, FB23-2 displayed a favorable pharmacokinetic profile and exhibited therapeutic efficacy in treating a patient-derived xeno-transplantation AML mouse model. Importantly, this proof-of-concept study demonstrated that small molecules targeting oncogenic FTO demethylase may be an effective therapeutic strategy for the treatment of AML.

However, due to the activity and selectivity of inhibitors, target engagement of current inhibitors needs further explorations. As FTO-mediated demethylation has also been linked to a variety of cancer types, the findings may have a broad impact on cancer therapy by targeting epitranscriptomic RNA methylation.

The article Linker: https://www.sciencedirect.com/science/article/pii/S1535610819301515?via%3Dihub#abs0020

Small Molecule Targeting Oncogenic FTO Demethylase in Acute Myeloid Leukemia (Image by YANG Caiguang)

Contact: Prof. YANG Caiguang (yangcg@simm.ac.cn)

(Credit: HUANG Yue; Editor: PAN Peihua)