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 <1 nM in human leukemia cells. It achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.

中文翻译：

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发现MD-224是针对Chimera鼠双分2降解剂的一流，高效且有效的蛋白水解酶，能够实现完全持久的肿瘤消退。

人鼠双分钟2（MDM2）蛋白是肿瘤抑制因子p53的主要内源性细胞抑制剂，已被人们视为有吸引力的癌症治疗靶标。几种有效的，非肽，小分子的MDM2抑制剂目前正在临床开发中。在本文中，我们报告了基于蛋白水解靶向嵌合体（PROTAC）概念的小分子MDM2降解剂的设计，合成和评估。最有前途的化合物（MD-224）在人白血病细胞中有效诱导MDM2在<1 nM的浓度下快速降解。它在抑制RS4; 11细胞生长方面达到1.5 nM的IC50值，并且在一组白血病细胞系中也达到了低纳摩尔IC50值。在耐受性良好的剂量方案下，MD-224在小鼠的RS4; 11异种移植肿瘤模型中实现了体内完整而持久的肿瘤消退。