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

Abstract

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.

Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells

“…However, overexpression of wild type PRMT6 but not its catalytic mutant (V86K/D88A) increases levels of H3R2me2a, as well as H3R8me2a and H4R3me2a (Figure 5A). There are several inhibitors that inhibit PRMT6 activity with different potency and selectivity: selective, allosteric PRMT6 inhibitor SGC6870 18 , PRMT type I inhibitor MS023 8 , and PRMT4/6 inhibitor MS049 9 . All of these inhibited PRMT6 dependent H3R2 (Figure 5B), as well as H4R3 and H3R8 asymmetric dimethylation (data not shown).…”