2. Academic Validation
  3. A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6

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

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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