2. Academic Validation
  3. Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening

Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening

  • J Med Chem. 2016 Jul 28;59(14):6838-47. doi: 10.1021/acs.jmedchem.6b00668.
Renato Ferreira de Freitas 1,  Mohammad S Eram 1,  David Smil 1,  Magdalena M Szewczyk 1,  Steven Kennedy 1,  Peter J Brown 1,  Vijayaratnam Santhakumar 1,  Dalia Barsyte-Lovejoy 1,  Cheryl H Arrowsmith 1 2,  Masoud Vedadi 1 3,  Matthieu Schapira 1 3
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
  • 2 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada.
  • 3 Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
PMID: 27390919 DOI: 10.1021/acs.jmedchem.6b00668
Abstract

Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and Other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC50 of 50 nM and more than hundred-fold selectivity over other PRMTs. These results indicate that virtual screening strategies can be successfully applied to Rossmann-fold protein methyltransferases.

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