title: Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor.
abstract: SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Lorna H
authors.initials: LH
authors.lastname: Mitchell
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Sherri
authors.initials: S
authors.lastname: Smith
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomenius
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Munchhof
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Mills
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Klaus
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Totman
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Riera
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Jacques
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Kip
authors.initials: K
authors.lastname: West
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Foley
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
keywords: KMT; SMYD3; methyltransferase; oncology; oxindole; tool compound