METTL3 is a member of a family of methyltransferase enzymes that use S-adenosyl methionine as a co-factor to methylate their substrates. In this case, the target substrates are adenosine residues, and the reaction products are modified nucleotides (M6A) held within specific RNA sequences. The wider biological function is post-transcriptional control of gene expression, and as METTL3 has been linked to the regulation of oncogenes and suppressors of apoptosis, it has great potential as a target for cancer therapeutics.

This webinar describes a collaborative effort between Epics therapeutics and Cresset Discovery, in which initial computational analysis and modelling facilitated the in-silico design that provided a potent, active and tractable METTL3 inhibitor hit for medicinal chemistry. This starting point, through DMTA cycles with multi-parameter optimisation, culminated in the successful development of a proof-of-concept molecule demonstrating efficacy in in-vivo models.

Read the full paper: Dutheuil et al, J. Med. Chem. 2025, 68, 3, 2981–3003.