染色质衍生物作为靶向胶质母细胞瘤的CRM1抑制剂。

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
ChemBioChem Pub Date : 2025-04-23 DOI:10.1002/cbic.202500195
Wolfgang Link, Salvatore Princiotto, Lucía Jiménez, Lucía Domínguez, João G N Sequeira, Cristiana Mourato, Alba Orea-Soufi, Bruno Santos, Sabrina Dallavalle, Miguel Machuqueiro, Bibiana I Ferreira
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引用次数: 0

摘要

胶质母细胞瘤(GBM)是最具侵袭性和致命性的癌症之一。由于GBM信号网络的复杂性和冗余性,特定途径的靶向抑制剂仅显示出有限的成功。核输出受体染色体区域维持1 (CRM1)最近成为一个有希望的治疗靶点,因为它的抑制可以同时破坏多个关键的致癌驱动因素。在这项研究中,我们探讨了以检测含硫醇分子而闻名的染色体衍生物是否可以作为CRM1抑制剂发挥作用。我们合成了几种基于染色体的衍生物,并证明它们以结构和剂量依赖的方式抑制crm1驱动的核输出。初步建立了构效关系(SAR),为基于分子对接研究的CRM1选择性结合提供了理论依据。此外,我们发现活性染色体衍生物能有效抑制胶质母细胞瘤细胞内源性核输出信号(NES)底物的核输出。其中一些化合物对胶质母细胞瘤细胞系表现出选择性细胞毒性,突出了它们作为GBM靶向治疗的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chromenone derivatives as CRM1 Inhibitors for Targeting Glioblastoma.

Glioblastoma (GBM) is one of the most aggressive and deadly cancers. Due to the complexity and redundancy within signaling networks in GBM, targeted inhibitors of specific pathways have shown only limited success. The nuclear export receptor Chromosome Region Maintenance 1 (CRM1) has recently emerged as a promising therapeutic target, as its inhibition can simultaneously disrupt multiple key oncogenic drivers. In this study, we explore whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors. We synthesized several chromenone-based derivatives and demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure-activity relationship (SAR) was established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, we showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal (NES)-containing substrates in glioblastoma cells. Several of these compounds exhibit selective cytotoxicity against glioblastoma cell lines, highlighting their potential as targeted therapies for GBM.

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来源期刊
ChemBioChem
ChemBioChem 生物-生化与分子生物学
CiteScore
6.10
自引率
3.10%
发文量
407
审稿时长
1 months
期刊介绍: ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).
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