Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression
Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression
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DOI：
10.1021/acs.jmedchem.8b00909
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发表时间：
2019-01-24
影响因子：
7.3
通讯作者：
Wang, Shaomeng
中科院分区：
文献类型：
--
作者：
Li, Yangbing;Yang, Jiuling;Wang, Shaomeng
人鼠双微体2（MDM 2）蛋白是肿瘤抑制因子p53的主要内源性细胞抑制剂，并且已被追求为有吸引力的癌症治疗靶点。几种有效的非肽类小分子MDM 2抑制剂目前正在临床开发中。在本文中，我们报告了我们的设计，合成和评估的小分子MDM 2降解剂的蛋白水解靶向嵌合体（PROTAC）的概念的基础上。最有希望的化合物（MD-224）在一定浓度下有效诱导MDM 2快速降解
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations