2. Academic Validation
  3. Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

  • J Med Chem. 2023 Aug 10. doi: 10.1021/acs.jmedchem.3c01030.
Alessandra Feoli 1,  Giulia Iannelli 1 2,  Alessandra Cipriano 1,  Ciro Milite 1,  Lei Shen 3,  Zhihao Wang 3,  Andrea Hadjikyriacou 4,  Troy L Lowe 4,  Cyrus Safaeipour 4,  Monica Viviano 1,  Giuliana Sarno 1 2,  Elva Morretta 5,  Maria Chiara Monti 5,  Yanzhong Yang 3,  Steven G Clarke 4,  Sandro Cosconati 6,  Sabrina Castellano 1,  Gianluca Sbardella 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno, via Giovanni Paolo II 132, Fisciano ,I-84084 SA Italy.
  • 2 PhD Program in Drug Discovery and Development, University of Salerno, via Giovanni Paolo II 132, Fisciano ,I-84084 SA Italy.
  • 3 Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, California 91010, United States.
  • 4 Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, California 90095, United States.
  • 5 Department of Pharmacy, ProteoMass Lab, University of Salerno, via Giovanni Paolo II 132, Fisciano ,I-84084 SA Italy.
  • 6 DiSTABiF, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy.
PMID: 37560786 DOI: 10.1021/acs.jmedchem.3c01030
Abstract

Less studied than the other protein arginine methyltransferase isoforms, PRMT7 and PRMT9 have recently been identified as important therapeutic targets. Yet, most of their biological roles and functions are still to be defined, as well as the structural requirements that could drive the identification of selective modulators of their activity. We recently described the structural requirements that led to the identification of potent and selective PRMT4 inhibitors spanning both the substrate and the cosubstrate pockets. The reanalysis of the data suggested a PRMT7 preferential binding for shorter derivatives and prompted us to extend these structural studies to PRMT9. Here, we report the identification of the first potent PRMT7/9 inhibitor and its binding mode to the two PRMT enzymes. Label-free quantification mass spectrometry confirmed significant inhibition of PRMT activity in cells. We also report the setup of an effective AlphaLISA assay to screen small molecule inhibitors of PRMT9.

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