Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability

Zhuqian Wang, Siran Yue, Xinxin Chen, Jin Li, Peixi Zhu, Hongzhen Chen, Fang Qiu, Duoli Xie, Yiying Liang, Defang Li*, Aiping Lu*, Chao Liang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.

Original languageEnglish
Pages (from-to)18865-18882
Number of pages18
JournalJournal of Medicinal Chemistry
Volume67
Issue number21
DOIs
Publication statusPublished - 14 Nov 2024

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

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