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 - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2022

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

Giulia Iannelli
  • Function : Author
Ciro Milite
  • Function : Author
Alessandra Feoli
  • Function : Author
Donatella Rescigno
  • Function : Author
Yalong Wang
  • Function : Author
Alessandra Cipriano
  • Function : Author
Monica Viviano
  • Function : Author
Mark Bedford
  • Function : Author
Sabrina Castellano
  • Function : Author
Gianluca Sbardella
  • Function : Author

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.
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Dates and versions

hal-04116086 , version 1 (02-06-2023)

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Giulia Iannelli, Ciro Milite, Nils Marechal, Vincent Cura, Luc Bonnefond, et al.. 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. Journal of Medicinal Chemistry, 2022, 65 (17), pp.11574-11606. ⟨10.1021/acs.jmedchem.2c00252⟩. ⟨hal-04116086⟩
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