新型吡咯并脲骨架ERK1/2抑制剂SHR2415的发现
Discovery of SHR2415, a Novel Pyrrole-Fused Urea Scaffold ERK1/2 Inhibitor.
作者信息
Li Xin, Dong Ping, Zhang Ting, Cai Guodong, Chen Yang, Dong Huaide, Yang Fang, Zhang Lei, Mao Yuchang, Feng Jun, Bai Chang, He Feng, Tao Weikang
机构信息
R&D Center, Shanghai Hengrui Pharmaceutical Co., LTD., 279 Wenjing Road, Shanghai 200245, China.
出版信息
ACS Med Chem Lett. 2022 Apr 1;13(4):701-706. doi: 10.1021/acsmedchemlett.2c00029. eCollection 2022 Apr 14.
Abstract
ERK1/2 kinase is a key downstream node of the RAS-RAF-MEK-ERK signaling pathway. A highly potent and selective ERK1/2 inhibitor is a promising option for cancer treatment that will provide a potential solution for overcoming drug resistance. Herein we designed and synthesized a novel scaffold featuring a pyrrole-fused urea template. The lead compound, SHR2415, was shown to be a highly potent ERK1/2 inhibitor that exhibited high cell potency based on the Colo205 assay. In addition, SHR2415 displayed favorable PK profiles across species as well as robust efficacy in a mouse Colo205 xenograft model.
摘要
ERK1/2激酶是RAS-RAF-MEK-ERK信号通路的关键下游节点。一种高效且选择性的ERK1/2抑制剂是癌症治疗的一个有前景的选择，它将为克服耐药性提供潜在的解决方案。在此，我们设计并合成了一种具有吡咯稠合脲模板的新型骨架。先导化合物SHR2415被证明是一种高效的ERK1/2抑制剂，基于Colo205试验显示出高细胞活性。此外，SHR2415在不同物种中表现出良好的药代动力学特征，并且在小鼠Colo205异种移植模型中具有强大的疗效。
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