2. Academic Validation
  3. MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell

MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell

  • Cell Death Discov. 2025 Mar 20;11(1):109. doi: 10.1038/s41420-025-02392-1.
Zheng Yuan # 1 2,  Meixia Guo # 1 2,  Yue Zhang # 1 2,  Yilin Deng # 1 2 3,  Biao Sun 1 2,  Yaning Hou 1 2,  Xin Wang 1 2,  Xiong Jin 1 2,  Yang Liu 4 5,  Bingyang Shi 6 7,  Jinlong Yin 8 9 10
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 2 Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 3 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
  • 4 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China. liuyang.jcbi@henu.edu.cn.
  • 5 Huaihe Hospital of Henan University, Kaifeng, China. liuyang.jcbi@henu.edu.cn.
  • 6 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China. bingyang.shi@mq.edu.au.
  • 7 Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China. bingyang.shi@mq.edu.au.
  • 8 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China. jlyin@henu.edu.cn.
  • 9 Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China. jlyin@henu.edu.cn.
  • 10 Huaihe Hospital of Henan University, Kaifeng, China. jlyin@henu.edu.cn.
  • # Contributed equally.
PMID: 40113745 DOI: 10.1038/s41420-025-02392-1
Abstract

Glioblastoma (GBM) stands as the most fatal brain tumor due to limited therapeutic options and high rates of drug resistance. Current surgical and pharmacological interventions usually fail to eradicate the aggressive GBM stem cells (GSCs), which leads to the deadly GBM occurrence. Although proteolysis-targeting chimeras (PROTACs) are prosperous in drug development for tumors, their application in GBM, particularly for GSC-sensitive drug candidates remains in its nascent stages. In this regard, we designed a monoacylglycerol Lipase (MAGL) targeting PROTAC, where MAGL was identified as a novel target for GSCs in our previous study. The MAGL Inhibitor JZL184 was redesigned by leveraging computational chemistry analysis, and an active unit was engaged for conjugation. E3 ligand for MAGL targeted warhead conjugation was screened with bioinformatics analyses, which revealed heightened activity of the E3 Ligase MDM2 in GBM, a classic negative regulator of the tumor suppressor P53, which correlates with patient prognosis. Then the PROTAC was conjugated with JZL184 analog and the MDM2 Inhibitor Nutlin-3 analog. Experimental results validated that the designed JN-PROTAC effectively induced MAGL targeted degradation and concomitantly enhanced P53 activation via MDM2 inhibition and is capable of inhibiting the progression of patient-derived GSCs in vivo. This work presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM.

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