Research On Small Molecule Inhibitors Of MRNA Demethylase FTO

As a dynamic and reversible epigenetic modification,m~6A exists on almost mRNAs and non-coding RNAs and closely related to physiological and pathological processes,including tumorigenesis.The fat mass and obesity-associated protein(FTO)participates in the homeostatic regulation of cellular m~6A through oxidatively demethylates the m~6A modification.However,the high expression of demethylase FTO is closely to pancreatic cancer and lung cancer,so small-molecule targeting of mRNA methylation modification-related proteins can be used as a new anti-tumor strategy.In this study,meclofenamic acid(MA)was used as a lead compound to improve the activity and selectivity of the compounds through using structure-guided drug design concepts.Fully utilize high-quality structural biology technology to reveal the binding mode and mechanism of MA derivatives and FTO protein from atomic accuracy.Evaluation of the activity of MA derivatives at the enzymatic and cellular level.We identified that one of the MA derivatives can effectively inhibits the proliferation of a variety of cancer cells(eg,pancreatic cancer,lung cancer,etc.)and increases the level of m~6A in cell.Meanwhile,high-throughput screening FTO inhibitors were performed by using fluorescence polarization for approximately 6,000 compounds provided by the National Compound Sample Bank and the cooperative research groups.We proved that one of the novel new skeleton compound can inhibits the demethylation of FTO and shows an inhibitory effect on the proliferation of a variety of lung cancer cells.In summary,our studies provide a theoretical basis for the design and synthesis of small molecule inhibitors of mRNA demethylase FTO,and provides small molecule tools for related research on mRNA modification.