title: Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy.
abstract: Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2MUTpreclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 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 , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Jeff
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
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 , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Xingnian
authors.initials: X
authors.lastname: Fu
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Chunye
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Feng
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Man
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Zhenting
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Xianghui
authors.identifier: 0000-0002-2230-8642
authors.initials: X
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Douglas
authors.initials: D
authors.lastname: Fang
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Haibing
authors.initials: H
authors.lastname: Guo
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gabriel
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 , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
authors.forename: Counde
authors.initials: C
authors.lastname: Oyang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D000882:Haplorhini; D006657:Histones / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C491488:EED protein, human; C000618736:EED226; D006657:Histones; D013450:Sulfones; D014230:Triazoles; D063151:Polycomb Repressive Complex 2; D008239:Lysine