Proteolysis targeting chimeras (PROTACs) have gained tremendous interest in both the academic and pharmaceutical communities. This opens a new way to regulate the cellular protein homeostasis, especially for disease-related proteins. In this work, we designed and synthesized a series of MDM2 degraders based on ligands that were readily prepared by a four-component Ugi reaction. After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines. Surprisingly, our mechanistic investigations indicated that WB214 not only effectively induced the degradation of MDM2, but also led to the degradation of p53. Further studies revealed that WB214 degraded MDM2 as a molecular glue. WB214 and its related analogues did not bind to MDM2 in the p53 binding region and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Finally, we found that WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth. A selective degrader for GSPT1 over MDM2 was then developed through systematically varying different motifs.

蛋白水解靶向嵌合体 (PROTAC) 引起了学术界和制药界的极大兴趣。这开辟了调节细胞蛋白质稳态的新方法，特别是与疾病相关的蛋白质。在这项工作中，我们设计并合成了一系列基于配体的 MDM2 降解剂，这些配体很容易通过四组分 Ugi 反应制备。经过基于抗增殖和 MDM2 降解的广泛优化， WB214被确定为各种白血病细胞系中最有效的抗增殖剂。令人惊讶的是，我们的机制研究表明WB214不仅有效诱导MDM2的降解，而且还导致p53的降解。进一步的研究表明， WB214将 MDM2 降解为分子胶。 WB214及其相关类似物不与 p53 结合区域中的 MDM2 结合，并且 MDM2 被发现是 E3 连接酶 cereblon 的新底物。最后，我们发现WB214可以有效降解 GSPT1，从而合理地抑制细胞生长。然后通过系统地改变不同的基序，开发了针对 MDM2 的 GSPT1 选择性降解剂。