A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6
Yudao Shen, Fengling Li, Magdalena M. Szewczyk, Levon Halabelian, Irene Chau, Mohammad S. Eram, Carlo dela Seña, Kwang‐Su Park, Fanye Meng, He Chen, Hong Zeng, Aiping Dong, Hong Wu, Viacheslav V. Trush, David McLeod, Carlos Zepeda‐Velázquez, Robert M. Campbell, Mary M. Mader, Brian M. Watson, Matthieu Schapira, C.H. Arrowsmith, Rima Al‐awar, Dalia Baršytė-Lovejoy, H. Ümit Kanıskan, Peter J. Brown, Masoud Vedadi, Jian Jin
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, (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.