Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

Kenneth W Duncan; Nathalie Rioux; P Ann Boriack-Sjodin; Michael J Munchhof; Lawrence A Reiter; Christina R Majer; Lei Jin; L Danielle Johnston; Elayne Chan-Penebre; Kristy G Kuplast; Margaret Porter Scott; Roy M Pollock; Nigel J Waters; Jesse J Smith; Mikel P Moyer; Robert A Copeland; Richard Chesworth

doi:10.1021/acsmedchemlett.5b00380

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

ACS Med Chem Lett. 2015 Dec 2;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380. eCollection 2016 Feb 11.

Authors

Kenneth W Duncan¹, Nathalie Rioux¹, P Ann Boriack-Sjodin¹, Michael J Munchhof¹, Lawrence A Reiter¹, Christina R Majer¹, Lei Jin¹, L Danielle Johnston¹, Elayne Chan-Penebre¹, Kristy G Kuplast¹, Margaret Porter Scott¹, Roy M Pollock¹, Nigel J Waters¹, Jesse J Smith¹, Mikel P Moyer¹, Robert A Copeland¹, Richard Chesworth¹

Affiliation

¹ Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.

Abstract

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).

Keywords: Methyltransferase; PRMT5; property based optimization; structure guided design.