Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

Lorna H Mitchell; Allison E Drew; Scott A Ribich; Nathalie Rioux; Kerren K Swinger; Suzanne L Jacques; Trupti Lingaraj; P Ann Boriack-Sjodin; Nigel J Waters; Tim J Wigle; Oscar Moradei; Lei Jin; Tom Riera; Margaret Porter-Scott; Mikel P Moyer; Jesse J Smith; Richard Chesworth; Robert A Copeland

doi:10.1021/acsmedchemlett.5b00071

Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

ACS Med Chem Lett. 2015 Apr 6;6(6):655-9. doi: 10.1021/acsmedchemlett.5b00071. eCollection 2015 Jun 11.

Authors

Lorna H Mitchell¹, Allison E Drew¹, Scott A Ribich¹, Nathalie Rioux¹, Kerren K Swinger¹, Suzanne L Jacques¹, Trupti Lingaraj¹, P Ann Boriack-Sjodin¹, Nigel J Waters¹, Tim J Wigle¹, Oscar Moradei¹, Lei Jin¹, Tom Riera¹, Margaret Porter-Scott¹, Mikel P Moyer¹, Jesse J Smith¹, Richard Chesworth¹, Robert A Copeland¹

Affiliation

¹ Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02138, United States.

Abstract

A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies.

Keywords: PRMT6; oncology; protein methyltransferase; tool compound.