The methylation of arginine residues is a prevalent posttranslational modification found in both nuclear and cytoplasmic proteins, which is involved in a number of different cellular processes, including transcriptional regulation, RNA metabolism, and DNA damage repair. Enzymes of the protein arginine N-methyltransferase (PRMTs) family catalyze the transfer of a methyl group from the donor S-adenosyl-l-methionine (SAM or AdoMet) to the guanidinium side chain of arginine residues in the target protein. Despite extensive research aimed at better understand the role of PRMTs in physiological and pathological pathways, there have been only a few publications to date describing small-molecule chemical modulators of the PRMTs. A few years ago, starting from AMI-1 (the first selective inhibitor of PRMTs) we identified EML108, which was characterized by an improved selectivity profile among methyltransferases and a good cellular activity. Moreover, docking studies clearly showed that EML108 bind SAM and arginine pocket without fully occupying them. Starting from this evidence, we herein report the design and the synthesis of new PRMTs inhibitors based on the naphthalene scaffold of EML108. Firstly, we prepared some derivatives bearing a guanidine moiety connected to the naphthalene scaffold via a variable linker. After optimization, we further functionalized this scaffold with an adenosine moiety. This multi-substrate-adduct approach lead to the identification of new sub-micromolar inhibitors of PRMTs.
|Titolo:||Identification of new inhibitors of PRMTs by a multi-substrate-adduct approach|
SBARDELLA, Gianluca (Corresponding)
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||4.3 Poster|