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Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy

Huang, Ying and Zhang, Jeff and Yu, Zhengtian and Wang, Youzhen and Lingel, Andreas and Qi, Vicky and Gu, Justin and Zhao, Kehao and Wang, Long and Fu, Xingnian and Sun, Yongfeng and Jiang, Xiangqing and Zhang, Jiangwei and Zhang, Chunye and Li, Ling and Liu, Yueqin and Zhang, Maya and Zhang, Lijun and Zhao, Mengxi and Fang, Douglas and Shultz, Michael and Mi, Yuan and Gao, Zhenting and Oyang, Counde and Zhang , Hailong and Liu , Xianghui and Zhang, Qiong and Zhang, Chao and Gou, Haibing and Dillon, Michael and Atadja, Peter and Zeng, Jue (2017) Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. Journal of Medicinal Chemistry, 60 (6). pp. 2215-2226. ISSN 1520-4804

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 EZH2MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

Item Type: Article
Date Deposited: 14 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/30365

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