title: EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.
abstract: Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.affiliation: Eisai Co., Ltd. , Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yokoi
authors.affiliation: Eisai Co., Ltd. , Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Eisai Co., Ltd. , Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Minoshima
authors.affiliation: Eisai, Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
authors.forename: Hyeong-Wook
authors.initials: HW
authors.lastname: Choi
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter Scott
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
keywords: B cell lymphoma; EZH2; KARPAS-422; Methyltransferase; PRC2; in vivo chemical probe; xenograft