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

Publication Type:

Journal Article


J Med Chem, Volume 64, Issue 7, p.3697-3706 (2021)


Allosteric Regulation, Allosteric Site, Benzodiazepinones, Crystallography, X-Ray, Enzyme Inhibitors, HEK293 Cells, Humans, Nuclear Proteins, Protein Binding, Protein-Arginine N-Methyltransferases, Stereoisomerism


<p>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, (SGC6870). is a potent PRMT6 inhibitor (IC = 77 &plusmn; 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6- complex and kinetic studies revealed binds a unique, induced allosteric pocket. Additionally, engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, &#39;s enantiomer, (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, - is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.</p>