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Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-02-06 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01576 Ying Huang 1 , Jeff Zhang 1 , Zhengtian Yu 1 , Hailong Zhang 1 , Youzhen Wang 1 , Andreas Lingel 2 , Wei Qi 1 , Justin Gu 1 , Kehao Zhao 1 , Michael D. Shultz 1 , Long Wang 1 , Xingnian Fu 1 , Yongfeng Sun 1 , Qiong Zhang 1 , Xiangqing Jiang 1 , Jiangwei Zhang 1 , Chunye Zhang 1 , Ling Li 1 , Jue Zeng 1 , Lijian Feng 1 , Chao Zhang 1 , Yueqin Liu 1 , Man Zhang 1 , Lijun Zhang 1 , Mengxi Zhao 1 , Zhenting Gao 1 , Xianghui Liu 1 , Douglas Fang 1 , Haibing Guo 1 , Yuan Mi 1 , Tobias Gabriel 1 , Michael P. Dillon 2 , Peter Atadja 1 , Counde Oyang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-02-06 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01576 Ying Huang 1 , Jeff Zhang 1 , Zhengtian Yu 1 , Hailong Zhang 1 , Youzhen Wang 1 , Andreas Lingel 2 , Wei Qi 1 , Justin Gu 1 , Kehao Zhao 1 , Michael D. Shultz 1 , Long Wang 1 , Xingnian Fu 1 , Yongfeng Sun 1 , Qiong Zhang 1 , Xiangqing Jiang 1 , Jiangwei Zhang 1 , Chunye Zhang 1 , Ling Li 1 , Jue Zeng 1 , Lijian Feng 1 , Chao Zhang 1 , Yueqin Liu 1 , Man Zhang 1 , Lijun Zhang 1 , Mengxi Zhao 1 , Zhenting Gao 1 , Xianghui Liu 1 , Douglas Fang 1 , Haibing Guo 1 , Yuan Mi 1 , Tobias Gabriel 1 , Michael P. Dillon 2 , Peter Atadja 1 , Counde Oyang 1
Affiliation
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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.
中文翻译：
发现具有强大抗癌功效的一流，有效和口服生物可利用的胚胎外胚层发育（EED）抑制剂
EZH2（多梳抑制复合物2（PRC2）的催化亚基）的过表达和体细胞杂合突变与几种肿瘤类型有关。EZH2抑制剂EPZ-6438（tazemetostat）在单药治疗的安全性可接受的患者中证明了临床疗效。EED，PRC2复合物的另一个亚基，通过直接与组蛋白3（H3K27Me3）上的三甲基化赖氨酸27结合，对其组蛋白甲基转移酶活性至关重要。本文中，我们公开了一流的有效，选择性和口服生物利用性EED抑制剂化合物43（EED226）的发现。在X射线晶体学的指导下，通过化合物7的断裂和再生长发现了化合物43，直接绑定EED的PRC2 HTS命中。随后的脚手架跳动和随后的多参数优化导致了43的发现。在EZH2 MUT临床前DLBCL模型中，化合物43诱导了强劲而持续的肿瘤消退。我们首次证明对EED的特异性和直接抑制可以有效地作为一种抗癌策略。
更新日期：2017-02-06
中文翻译：
发现具有强大抗癌功效的一流，有效和口服生物可利用的胚胎外胚层发育（EED）抑制剂
EZH2（多梳抑制复合物2（PRC2）的催化亚基）的过表达和体细胞杂合突变与几种肿瘤类型有关。EZH2抑制剂EPZ-6438（tazemetostat）在单药治疗的安全性可接受的患者中证明了临床疗效。EED，PRC2复合物的另一个亚基，通过直接与组蛋白3（H3K27Me3）上的三甲基化赖氨酸27结合，对其组蛋白甲基转移酶活性至关重要。本文中，我们公开了一流的有效，选择性和口服生物利用性EED抑制剂化合物43（EED226）的发现。在X射线晶体学的指导下，通过化合物7的断裂和再生长发现了化合物43，直接绑定EED的PRC2 HTS命中。随后的脚手架跳动和随后的多参数优化导致了43的发现。在EZH2 MUT临床前DLBCL模型中，化合物43诱导了强劲而持续的肿瘤消退。我们首次证明对EED的特异性和直接抑制可以有效地作为一种抗癌策略。
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