Inducing protein degradation by proteolysis targeting chimeras (PROTACs) has gained tremendous momentum for its promise to discover and develop new therapies. Based upon our previously reported PROTAC MDM2 degraders, we have designed and synthesized additional analogues. Surprisingly, we found that simple structural modifications of MD-222, a bona fide MDM2 PROTAC degrader, converts it into a “molecular glue”, as exemplified by MG-277. MG-277 induces only moderate MDM2 degradation and fails to activate wild-type p53 but is highly potent in inhibition of tumor cell growth in a p53-independent manner. Our mechanistic investigation established that MG-277 is not a PROTAC MDM2 degrader but instead works as a molecular glue, inducing degradation of a translation termination factor, GSPT1 to achieve its potent anticancer activity. Our study provides the first example that simple structural modifications can convert a bona fide PROTAC degrader into a molecular glue compound, which has a completely different mechanism of action.

中文翻译：

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简单的结构修饰，将真正的MDM2 PROTAC降解剂转化为分子胶分子：PROTAC降解剂设计中的警示故事。

通过针对嵌合体（PROTAC）的蛋白水解诱导蛋白质降解已获得了巨大的动力，因为它有望发现和开发新的疗法。基于我们先前报道的PROTAC MDM2降解物，我们设计并合成了其他类似物。令人惊讶地，我们发现，真正的MDM2 PROTAC降解剂MD-222的简单结构修饰将其转化为“分子胶”，如MG-277所示。MG-277仅诱导中等程度的MDM2降解，不能激活野生型p53，但以非p53的方式高度有效地抑制肿瘤细胞的生长。我们的机械调查确定了MG-277它不是PROTAC MDM2降解剂，而是充当分子胶，可诱导翻译终止因子GSPT1降解，以实现其强大的抗癌活性。我们的研究提供了第一个实例，即简单的结构修饰可以将真正的PROTAC降解剂转化为分子胶化合物，其作用机理完全不同。