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

Authors

Giulia Iannelli
Ciro Milite
Nils Marechal
Vincent Cura
Luc Bonnefond
Nathalie Troffer-Charlier
Alessandra Feoli
Donatella Rescigno
Yalong Wang
Alessandra Cipriano
Monica Viviano
Mark T Bedford
Jean Cavarelli
Sabrina Castellano
Gianluca Sbardella

Publication Date

9-8-2022

Journal

Journal of Medicinal Chemistry

Abstract

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.

Keywords

Arginine, Enzyme Inhibitors, Methylation, Protein Processing, Post-Translational, Protein-Arginine N-Methyltransferases

Comments

Supplementary Materials

PMID: 35482954