title: Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.
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).
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Duncan
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Majer
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: L Danielle
authors.initials: LD
authors.lastname: Johnston
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Elayne
authors.initials: E
authors.lastname: Chan-Penebre
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Kristy G
authors.initials: KG
authors.lastname: Kuplast
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter Scott
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
keywords: Methyltransferase; PRMT5; property based optimization; structure guided design