Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders

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.

通过蛋白水解靶向嵌合体（Proteolysis Targeting Chimeras，PROTACs）诱导蛋白质降解，因其在发现与开发新型治疗药物方面的巨大潜力而获得了迅猛发展。基于本团队此前报道的鼠双微体2（MDM2）靶向PROTAC降解剂，我们设计并合成了一系列新增类似物。令人意外的是，对一款经验证的MDM2靶向PROTAC降解剂MD-222进行简单的结构修饰，可将其转化为“分子胶”，MG-277即为典型代表。MG-277仅能诱导中等程度的MDM2降解，且无法激活野生型p53，但却能以p53非依赖的方式强效抑制肿瘤细胞增殖。我们的机制研究证实，MG-277并非MDM2靶向PROTAC降解剂，而是作为分子胶，通过诱导翻译终止因子GSPT1的降解来实现其强效的抗肿瘤活性。本研究首次证明，简单的结构修饰可将经验证的PROTAC降解剂转化为作用机制完全不同的分子胶类化合物。