Huang Ying, Zhang Jeff, Yu Zhengtian, Zhang Hailong, Wang Youzhen, Lingel Andreas, Qi Wei, Gu Justin, Zhao Kehao, Shultz Michael D, Wang Long, Fu Xingnian, Sun Yongfeng, Zhang Qiong, Jiang Xiangqing, Zhang Jiangwei, Zhang Chunye, Li Ling, Zeng Jue, Feng Lijian, Zhang Chao, Liu Yueqin, Zhang Man, Zhang Lijun, Zhao Mengxi, Gao Zhenting, Liu Xianghui, Fang Douglas, Guo Haibing, Mi Yuan, Gabriel Tobias, Dillon Michael P, Atadja Peter, Oyang Counde
Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
J Med Chem. 2017 Mar 23;60(6):2215-2226. doi: 10.1021/acs.jmedchem.6b01576. Epub 2017 Feb 6.
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 EZH2 preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.
多梳抑制复合物2（PRC2）的催化亚基EZH2的过表达和体细胞杂合突变与多种肿瘤类型相关。EZH2抑制剂EPZ-6438（他泽司他）作为单一疗法在患者中显示出临床疗效，且安全性可接受。EED是PRC2复合物的另一个亚基，通过直接结合组蛋白3上的三甲基化赖氨酸27（H3K27Me3）对其组蛋白甲基转移酶活性至关重要。在此，我们披露了首个具有强效、选择性和口服生物利用度的EED抑制剂化合物43（EED226）的发现。在X射线晶体学的指导下，通过对化合物7进行片段化和再生发现了化合物43，化合物7是PRC2高通量筛选的一个直接结合EED的活性化合物。随后的骨架跃迁以及多参数优化促成了43的发现。化合物43在EZH2临床前弥漫性大B细胞淋巴瘤（DLBCL）模型中诱导了强大且持续的肿瘤消退。我们首次证明，对EED进行特异性和直接抑制可作为一种有效的抗癌策略。
