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

in Cell death discovery by Zheng Yuan, Meixia Guo, Yue Zhang, Yilin Deng, Biao Sun, Yaning Hou, Xin Wang, Xiong Jin, Yang Liu, Bingyang Shi, Jinlong Yin

TLDR

  • The study designed a PROTAC, JN-PROTAC, that targets MAGL and inhibits MDM2 to induce MAGL degradation and enhance P53 activation, effectively inhibiting patient-derived GSCs in vivo, presenting a potential therapeutic strategy for GBM.

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.

Overview

  • The study aims to develop a proteolysis-targeting chimera (PROTAC) for glioblastoma (GBM) stem cells (GSCs) to overcome limited therapeutic options and drug resistance.
  • The study targets monoacylglycerol lipase (MAGL), a novel target for GSCs, and a PROTAC consisting of JZL184, a MAGL inhibitor, and MDM2, an E3 ligase targeting warhead conjugation, is designed.
  • The primary objective is to develop a PROTAC that effectively induces MAGL degradation, enhances P53 activation, and inhibits the progression of patient-derived GSCs in vivo.

Comparative Analysis & Findings

  • The designed JN-PROTAC demonstrated effective MAGL-targeted degradation and concomitant enhancement of P53 activation via MDM2 inhibition.
  • The study validated the induction of MAGL degradation and P53 activation in patient-derived GSCs in vitro and in vivo, suggesting the potential of JN-PROTAC for GBM treatment.
  • The improved activity of JN-PROTAC against GSCs was attributed to the synergistic effect of MAGL inhibition and MDM2 inhibition.

Implications and Future Directions

  • The study presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM.
  • Future studies should investigate the safety and efficacy of JN-PROTAC in clinical settings and explore its potential combination with existing therapies for improved treatment outcomes.
  • The identification of novel targets and PROTAC designs may further enhance the development of effective therapies for GBM, a fatal brain tumor with limited treatment options.
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