Synthesis of selective BCL-XL PROTAC and potent antitumor activity in glioblastoma

IF 6.9 2区综合性期刊 Q1 CHEMISTRY, MULTIDISCIPLINARY

Cell Reports Physical Science Pub Date : 2025-05-01 DOI:10.1016/j.xcrp.2025.102593

Meichen Liu, Biao Sun, Rui Niu, Yue Zhang, Xinyu Li, Jiefei Wang, Xin Wang, Jinlong Yin

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引用次数: 3

Abstract

Summary

Glioblastoma (GBM), the most aggressive and treatment-resistant form of brain cancer, is significantly influenced by GBM stem cells (GSCs), which contribute to tumor initiation and recurrence. This study introduces two innovative proteolysis-targeting chimeras (PROTACs), AN-1 and AN-2, designed to degrade BCL-X_L, a key anti-apoptotic protein in the BCL-2 family. Optimized from ABT-263, these PROTACs utilize MDM2 as an E3 ligase, a strategy not previously used in GBM therapy. Our approach leverages the high expression of MDM2 in GSCs and low expression in platelets, enhancing therapeutic specificity and reducing the risk of thrombocytopenia—a key side effect of BCL-X_L inhibition. Both in vitro and in vivo studies show that AN-1 and AN-2 effectively inhibit GSC proliferation, promote apoptosis, and significantly improve survival rates without inducing thrombocytopenia. This study highlights the potential of targeting underexplored E3 ligases in cancer therapy and offers a selective approach to treating GBM, overcoming current treatment limitations.

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选择性BCL-XL PROTAC的合成及其在胶质母细胞瘤中的抗肿瘤活性

胶质母细胞瘤（GBM）是最具侵袭性和治疗抵抗性的脑癌形式，它受GBM干细胞（GSCs）的显著影响，有助于肿瘤的发生和复发。本研究引入了两种创新的蛋白水解靶向嵌合体（PROTACs）， AN-1和AN-2，旨在降解BCL-XL， BCL-XL是BCL-2家族中的关键抗凋亡蛋白。这些PROTACs以ABT-263为基础进行优化，利用MDM2作为E3连接酶，这是一种以前未用于GBM治疗的策略。我们的方法利用了MDM2在GSCs中的高表达和血小板中的低表达，增强了治疗特异性并降低了血小板减少的风险——这是BCL-XL抑制的一个关键副作用。体外和体内研究均表明，AN-1和AN-2能有效抑制GSC增殖，促进细胞凋亡，显著提高生存率，且不诱导血小板减少。这项研究强调了靶向未开发的E3连接酶在癌症治疗中的潜力，并提供了一种治疗GBM的选择性方法，克服了目前的治疗局限性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Physical Science Energy-Energy (all)

CiteScore

11.40

自引率

2.20%

发文量

388

审稿时长

62 days

期刊介绍： Cell Reports Physical Science, a premium open-access journal from Cell Press, features high-quality, cutting-edge research spanning the physical sciences. It serves as an open forum fostering collaboration among physical scientists while championing open science principles. Published works must signify significant advancements in fundamental insight or technological applications within fields such as chemistry, physics, materials science, energy science, engineering, and related interdisciplinary studies. In addition to longer articles, the journal considers impactful short-form reports and short reviews covering recent literature in emerging fields. Continually adapting to the evolving open science landscape, the journal reviews its policies to align with community consensus and best practices.