title: The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat.
abstract: Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter-Scott
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Sneeringer
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Allain
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Majer
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Epizyme , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
mesh_terms: D000818:Animals; D055808:Drug Discovery; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation / Q000187:drug effects*; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D054852:Small Molecule Libraries; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2