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J Med Chem. 2016 Aug 25;59(16):7617-33. doi: 10.1021/acs.jmedchem.6b00855. Epub 2016 Aug 11.

Structure-Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors.

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Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , One Gustave L. Levy Place, Room 16-20B, Box 1677, New York, New York 10029, United States.
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 2M9, Canada.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.


EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.

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