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J Med Chem. 2018 Feb 8;61(3):1204-1217. doi: 10.1021/acs.jmedchem.7b01674. Epub 2018 Jan 5.

Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).

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Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China.
DiscoveRx Corporation , Fremont, California 94538, United States.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre , 101 College Street, MaRS South Tower, Suite 707, Toronto, ON M5G 1L7, Canada.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.


PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC50 values: ∼10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.

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