Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability
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.
Authors
- Hongzhen Chen (ORCID: https://orcid.org/0000-0001-7578-7248)
- Siran Yue (ORCID: https://orcid.org/0009-0001-7465-5486)
- Zhuqian Wang (ORCID: https://orcid.org/0000-0002-9190-9345)
- Chao Liang (ORCID: https://orcid.org/0000-0002-5617-3483)
- Peixi Zhu (ORCID: https://orcid.org/0000-0001-8380-4239)
- Defang Li (ORCID: https://orcid.org/0000-0003-4151-9151)
- Xinxin Chen (ORCID: https://orcid.org/0000-0003-3929-2314)
- Jin Li (ORCID: https://orcid.org/0000-0002-7957-1476)
- Yiying Liang (ORCID: https://orcid.org/0009-0007-4704-5141)
- Fang Qiu (ORCID: https://orcid.org/0000-0002-5673-3858)
- Aiping Lu
- Duoli Xie
Institutions
- Binzhou Medical University (CN)
- Hong Kong Baptist University (HK)
- Shandong University of Aeronautics (CN)
- Southern University of Science and Technology (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Beijing Proteome Research Center (CN)
- State Key Laboratory of Proteomics
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01228
- Citations
- 7
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- National Natural Science Foundation of China
- Research Grants Council, University Grants Committee
- Science, Technology and Innovation Commission of Shenzhen Municipality
- Basic and Applied Basic Research Foundation of Guangdong Province