Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

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.