A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

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Author(s)

Author Name

Yudao Shen

Published 2 Projects

Biochemistry

Uploader

Fengling Li

Magdalena Szewczyk

Levon Halabelian

Published 2 Projects

Biochemistry

Irene Chau

Published 3 Projects

Biochemistry Cell Biology

Mohammad S. Eram

Published 1 Project

Biochemistry

Carlo Dela Sena

Published 1 Project

Biochemistry

Kwang-Su Park

Published 1 Project

Biochemistry

Fanye Meng

Published 1 Project

Biochemistry

He Chen

Published 1 Project

Biochemistry

David McLeod

Carlos A. Zepeda-Velazquez

Published 1 Project

Biochemistry

Robert M. Campbell

Published 1 Project

Biochemistry

Mary M. Mader

Published 1 Project

Biochemistry

Brian M. Watson

Published 1 Project

Biochemistry

Matthieu Schapira

Associate Professor, University of Toronto

Published 8 Projects

Bioinformatics Biochemistry Pharmacology And Toxicology Cell Biology

Rima Al-Awar

H. Umit Kaniskan

Published 1 Project

Biochemistry

Peter J Brown

Masoud Vedadi

Jian Jin

Published 3 Projects

Biochemistry

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

Biochemistry
Biochemistry 9 Projects