Protein arginine
methyltransferases (PRMTs) are important therapeutic
targets, playing a crucial role in the regulation of many cellular
processes and being linked to many diseases. Yet, there is still much
to be understood regarding their functions and the biological pathways
in which they are involved, as well as on the structural requirements
that could drive the development of selective modulators of PRMT activity.
Here we report a deconstruction–reconstruction approach that,
starting from a series of type I PRMT inhibitors previously identified
by us, allowed for the identification of potent and selective inhibitors
of PRMT4, which regardless of the low cell permeability show an evident
reduction of arginine methylation levels in MCF7 cells and a marked
reduction of proliferation. We also report crystal structures with
various PRMTs supporting the observed specificity and selectivity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.