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

2015; American Chemical Society; Volume: 6; Issue: 6 Linguagem: Inglês

10.1021/acsmedchemlett.5b00071

1948-5875

Lorna H. Mitchell, Allison E. Drew, Scott 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, Thomas V. Riera, Margaret Porter-Scott, Mikel P. Moyer, J. Joshua Smith, Richard Chesworth, Robert A. Copeland,

Epigenetics and DNA Methylation

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.