2. Academic Validation
  3. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3)

A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3)

  • Angew Chem Int Ed Engl. 2015 Apr 20;54(17):5166-70. doi: 10.1002/anie.201412154.
H Ümit Kaniskan 1,  Magdalena M Szewczyk,  Zhengtian Yu,  Mohammad S Eram,  Xiaobao Yang,  Keith Schmidt,  Xiao Luo,  Miao Dai,  Feng He,  Irene Zang,  Ying Lin,  Steven Kennedy,  Fengling Li,  Elena Dobrovetsky,  Aiping Dong,  David Smil,  Sun-Joon Min,  Melissa Landon,  Jennifer Lin-Jones,  Xi-Ping Huang,  Bryan L Roth,  Matthieu Schapira,  Peter Atadja,  Dalia Barsyte-Lovejoy,  Cheryl H Arrowsmith,  Peter J Brown,  Kehao Zhao,  Jian Jin,  Masoud Vedadi
Affiliations

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).
PMID: 25728001 DOI: 10.1002/anie.201412154
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.

Keywords

X-ray diffraction; allosteric inhibition; chemical probes; enzyme inhibitors; histone methylation.

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