A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6

  • J Med Chem. 2021 Apr 8;64(7):3697-3706. doi: 10.1021/acs.jmedchem.0c02160.
Yudao Shen  1 ,  Fengling Li  2 ,  Magdalena M Szewczyk  2 ,  Levon Halabelian  2 ,  Irene Chau  2 ,  Mohammad S Eram  2 ,  Carlo Dela Seña  2 ,  Kwang-Su Park  1 ,  Fanye Meng  1 ,  He Chen  1 ,  Hong Zeng  2 ,  Aiping Dong  2 ,  Hong Wu  2 ,  Viacheslav V Trush  2 ,  David McLeod  3 ,  Carlos A Zepeda-Velázquez  3 ,  Robert M Campbell  4 ,  Mary M Mader  4 ,  Brian M Watson  4 ,  Matthieu Schapira  2 ,  Cheryl H Arrowsmith  2  5 ,  Rima Al-Awar  3 ,  Dalia Barsyte-Lovejoy  2 ,  H Ümit Kaniskan  1 ,  Peter J Brown  2 ,  Masoud Vedadi  2  6 ,  Jian Jin  1
Affiliations
  • 1. Mount Sinai Center for Therapeutics 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.
  • 2. Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3. Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • 4. Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46225, United States.
  • 5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 6. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
PMID: 33591753 DOI: 10.1021/acs.jmedchem.0c02160
Abstract

Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 Inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 Inhibitor (IC50 = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of Other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6-(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2's enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.

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