Lu Biao, Shen Xiaodong, Zhang Lei, Liu Dong, Zhang Caihua, Cao Jingsong, Shen Ru, Zhang Jiayin, Wang Dan, Wan Hong, Xu Zhibin, Ho Ming-Hsun, Zhang Minsheng, Zhang Lianshan, He Feng, Tao Weikang
Shanghai Hengrui Pharmaceutical Co. Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China.
Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States.
ACS Med Chem Lett. 2018 Jan 29;9(2):98-102. doi: 10.1021/acsmedchemlett.7b00437. eCollection 2018 Feb 8.
A novel series of benzofuran derived EZH2 inhibitors were discovered through a scaffold hopping approach based on the clinical compound of EPZ-6438. Further rational structure-activity relationship exploration and optimization led to the discovery of more potent EZH2 inhibitors with oral bioavailability in mice and rats. A lead compound (compound ) demonstrated excellent efficacy in Pfeiffer tumor Xenograft models in mouse and is under preclinical development for the treatment of cancers associated with EZH2 mutations.
通过基于临床化合物EPZ-6438的骨架跃迁方法，发现了一系列新型的苯并呋喃衍生的EZH2抑制剂。进一步合理的构效关系探索和优化导致发现了在小鼠和大鼠中具有口服生物利用度的更有效的EZH2抑制剂。一种先导化合物（化合物 ）在小鼠的Pfeiffer肿瘤异种移植模型中显示出优异的疗效，并且正在进行临床前开发，用于治疗与EZH2突变相关的癌症。
