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

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, <i>(R)-</i><b>2</b> (SGC6870). <i>(R)-</i><b>2</b> 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-<i>(R)-</i><b>2</b> complex and kinetic studies revealed <i>(R)-</i><b>2</b> binds a unique, induced allosteric pocket. Additionally, <i>(R)-</i><b>2</b> engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, <i>(R)-</i><b>2</b>'s enantiomer, <i>(S)-</i><b>2</b> (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, <i>(R)</i>-<b>2</b> is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.