A Potent,Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3) |
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| Authors: | Dr. H. Ümit Kaniskan Dr. Magdalena M. Szewczyk Dr. Zhengtian Yu Dr. Mohammad S. Eram Dr. Xiaobao Yang Keith Schmidt Dr. Xiao Luo Miao Dai Dr. Feng He Irene Zang Dr. Ying Lin Dr. Steven Kennedy Dr. Fengling Li Elena Dobrovetsky Aiping Dong Dr. David Smil Dr. Sun‐Joon Min Dr. Melissa Landon Dr. Jennifer Lin‐Jones Dr. Xi‐Ping Huang Prof. Dr. Bryan L. Roth Prof. Dr. Matthieu Schapira Dr. Peter Atadja Dr. Dalia Barsyte‐Lovejoy Prof. Dr. Cheryl H. Arrowsmith Dr. Peter J. Brown Dr. Kehao Zhao Prof. Dr. Jian Jin Prof. Dr. Masoud Vedadi |
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| Affiliation: | 1. Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (USA);2. Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7 (Canada);3. Novartis Institutes for Biomedical Research (China), Zhangjiang Hi‐Tech Park, Pudong New Area, Shanghai 201203 (China);4. Center for Neuro‐Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul 136‐791 (South Korea);5. DiscoveRx Corporation, Fremont, CA 94538 (USA);6. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC27599 (USA);7. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8 (Canada);8. Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, 101 College St., MaRS South Tower, Suite 707, Toronto, ON M5G 1L7 (Canada) |
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| Abstract: | ![]()
PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell‐active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure‐based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50=31±2 nM , KD=53±2 nM ) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non‐epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3‐SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well‐characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease. |
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| Keywords: | allosteric inhibition chemical probes enzyme inhibitors histone methylation X‐ray diffraction |
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