Identification of Small-Molecule
Enhancers of Arginine Methylation Catalyzed by Coactivator-Associated
Arginine Methyltransferase 1
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Abstract
Arginine methylation is a common post-translational modification
that is crucial in modulating gene expression at multiple critical
levels. The arginine methyltransferases (PRMTs) are envisaged as promising
druggable targets, but their role in physiological and pathological
pathways is far from being clear due to the limited number of modulators
reported to date. In this effort, enzyme activators can be invaluable
tools useful as gain-of-function reagents to interrogate the biological
roles in cells and in vivo of PRMTs. Yet the identification of such
molecules is rarely pursued. Herein we describe a series of aryl ureido
acetamido indole carboxylates (dubbed “uracandolates”),
able to increase the methylation of histone (H3) or nonhistone (polyadenylate-binding
protein 1, PABP1) substrates induced by coactivator-associated arginine
methyltransferase 1 (CARM1), both in in vitro and cellular settings.
To the best of our knowledge, this is the first report of compounds
acting as CARM1 activators