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Identification of a Novel Small Molecule Inhibitor of the RNA Demethylase FTO using MST

N-6-methyladenosine (m6A) is the most abundant RNA chemical modification found in the eukaryotic transcriptome. It is a dynamic and reversible modification which plays a role in RNA function across a wide range of biological processes. Dysregulation of the m6A modification and the methyl handling enzymes involved have been implicated in the progression of multiple types of cancer and metabolic disease. RNA modifying enzymes are therefore emerging therapeutic targets. One of these potential targets is fat mass and obesity associated protein (FTO), a member of the non-heme dioxygenase superfamily and one of two ‘erasers’ responsible for demethylating m6A.

Microscale thermophoresis (MST) is a powerful solution-based biophysical technique for quantifying biomolecular interactions, which afforded significantly lower enzyme consumption than traditional FTO enzyme activity based screens. A robust MST assay was developed, validated, and used to screen 100 compounds from the LOPAC for novel human FTO small molecule binders. Five compounds, which displayed reproducible, concentration-dependent binding in the MST screen, were tested for inhibition of human FTO enzyme activity and revealed a single, novel FTO inhibitor. Our proof of concept study describes a robust, economical screening cascade for hit identification of the RNA modifying enzyme FTO.

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