2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Sep 8;65(17):11574-11606. doi: 10.1021/acs.jmedchem.2c00252.
Giulia Iannelli,  Ciro Milite,  Nils Marechal 1 2 3 4,  Vincent Cura 1 2 3 4,  Luc Bonnefond 1 2 3 4,  Nathalie Troffer-Charlier 1 2 3 4,  Alessandra Feoli,  Donatella Rescigno,  Yalong Wang 5,  Alessandra Cipriano,  Monica Viviano,  Mark T Bedford 5,  Jean Cavarelli 1 2 3 4,  Sabrina Castellano,  Gianluca Sbardella
Affiliations

Affiliations

  • 1 Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.
  • 2 Centre National de la Recherche Scientifique, UMR7104 Illkirch, France.
  • 3 Institut National de la Santé et de la Recherche Médicale, U1258 Illkirch, France.
  • 4 Université de Strasbourg, 67400 Illkirch, France.
  • 5 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 35482954 DOI: 10.1021/acs.jmedchem.2c00252
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.

Figures
Products