Design, synthesis and biological evaluation of new selective arginine methyltransferases (PRMTs) Inhibitors

The methylation of arginine residues is a prevalent posttranslational modification found in both nuclear and cytoplasmic proteins. Enzymes of the protein arginine N-methyltransferase (PRMTs) family catalyse the transfer of a methyl group from the donor S-adenosyl-l-methionine (SAM) to the guanidinium side chain of arginine residues in the target protein. Despite extensive research aimed to better understand the role of PRMTs in physiological and pathological pathways, to date there have been only a few publications describing small-molecule chemical modulators of the PRMTs. A few years ago, we identified EML108, which was characterized by an improved selectivity profile among methyltransferases and a good cellular activity (1). Moreover, docking studies clearly showed that EML108 bind SAM and arginine pockets without fully occupying them. With the aim to identify the suitable arginine-mimetic moieties, we resolved to use a deconstruction–reconstruction approach. We deconstructed our compounds and then performed a medicinal chemistry optimization campaign. The first series of molecules incorporate the 4-hydroxy-2-naphthoic group bridged by an amide or urea group with an arginine mimetic moiety. After optimization, we further functionalized this scaffold with an adenosine moiety. Here we report our multi-substrate-adduct approach that led to the identification of new sub-micromolar inhibitors of PRMTs.