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

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.