Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 16, Pages 7617-7633Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00855
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Funding
- U.S. National Institutes of Health [R01GM103893]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- SGC
- Medicinal Chemistry Division of the American Chemical Society
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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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