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
Copyright policy )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.
- Università degli studi di Salerno Italy
- Texas Medical Center United States
- Conférence des Présidents d'Université France
- French National Centre for Scientific Research France
- The University of Texas MD Anderson Cancer Center United States
570, Protein-Arginine N-Methyltransferases, Medical Sciences, Biochemical Phenomena, Bioinformatics, Post-Translational, 610, Small-molecule inhibitors; Histone/Protein methyltransferase; Functional insights; Histone H3; RGG box; Coactivator; Methylation; CARM1; Design; Assay, Medical Biochemistry, Arginine, Methylation, Biomedical Informatics, Metabolism, Oncology, Medical Specialties, Medicine and Health Sciences, Enzyme Inhibitors, Protein Processing, Post-Translational, Protein Processing, and Nutrition
570, Protein-Arginine N-Methyltransferases, Medical Sciences, Biochemical Phenomena, Bioinformatics, Post-Translational, 610, Small-molecule inhibitors; Histone/Protein methyltransferase; Functional insights; Histone H3; RGG box; Coactivator; Methylation; CARM1; Design; Assay, Medical Biochemistry, Arginine, Methylation, Biomedical Informatics, Metabolism, Oncology, Medical Specialties, Medicine and Health Sciences, Enzyme Inhibitors, Protein Processing, Post-Translational, Protein Processing, and Nutrition
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