title: Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.
abstract: PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Andreas
authors.identifier: 0000-0003-2909-4920
authors.initials: A
authors.lastname: Lingel
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Sendzik
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Ying
authors.identifier: 0000-0001-5265-3984
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: John
authors.initials: J
authors.lastname: Cantwell
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dillon
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Xingnian
authors.initials: X
authors.lastname: Fu
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: John
authors.initials: J
authors.lastname: Fuller
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gabriel
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liang
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Maureen
authors.initials: M
authors.lastname: McKenna
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Rao
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Shu
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: James
authors.initials: J
authors.lastname: Sutton
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Taft
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Maya
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 2418 Jinke Road, Shanghai 201203, China.
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Mika
authors.initials: M
authors.lastname: Lindvall
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Dirksen E
authors.initials: DE
authors.lastname: Bussiere
mesh_terms: D000494:Allosteric Regulation; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006801:Humans; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008780:Methyltransferases; D063151:Polycomb Repressive Complex 2