Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries

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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

PROTACs have attracted significant interest in academic and pharmaceutical communities for regulating cellular protein homeostasis. A series of MDM2 degraders were designed and synthesized, with WB214 identified as a potent anti-proliferative agent inducing the degradation of MDM2 and p53. Mechanistic studies revealed that WB214 functions as a molecular glue degrading MDM2, and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Additionally, WB214 could potently degrade GSPT1, leading to the development of a selective degrader for GSPT1 over MDM2.