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

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

  • J Med Chem. 2024 Nov 14;67(21):18865-18882. doi: 10.1021/acs.jmedchem.4c01228.
Zhuqian Wang 1 2,  Siran Yue 1 2,  Xinxin Chen 1,  Jin Li 1,  Peixi Zhu 1,  Hongzhen Chen 1,  Fang Qiu 1 2,  Duoli Xie 1 2,  Yiying Liang 3,  Defang Li 4,  Aiping Lu 2 5 6,  Chao Liang 1 2 7
Affiliations

Affiliations

  • 1 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
  • 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China.
  • 3 Shenzhen LingGene Biotech Co., Ltd., Shenzhen 518055, China.
  • 4 Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai 264003, China.
  • 5 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510006, China.
  • 6 Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
  • 7 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China.
PMID: 39437434 DOI: 10.1021/acs.jmedchem.4c01228
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.

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