从表型筛选中发现并优化氧化磷酸化抑制剂。

IF 2.2 4区 医学 Q3 ONCOLOGY
Anti-Cancer Drugs Pub Date : 2025-10-01 Epub Date: 2025-06-20 DOI:10.1097/CAD.0000000000001750
Mahmoud El Shemerly, Florian Richalet, Dimitri Robay, Claude Nuoffer, Alexandra Kunz, Luc Bury, Claire Hisler, Norbert Hermann, Jochen Spickermann, Sven Weiler, Paul M J McSheehy, Laurenz Kellenberger, Heidi A Lane
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引用次数: 0

摘要

肿瘤细胞的肿瘤代谢和代谢重编程是肿瘤研究的一个有前途的领域,为治疗干预提供了新的途径。虽然“Warburg效应”强调了许多肿瘤对有氧糖酵解的依赖,但新出现的证据表明,一些癌症也依赖线粒体氧化磷酸化(OXPHOS)来产生能量、癌细胞存活、肿瘤进展、转移和耐药性。我们进行了高通量、差异、表型筛选,随后进行了重点药物化学活动,从而鉴定出新的、有效的OXPHOS抑制剂。这些先导化合物选择性地靶向线粒体电子传递链的复合物I,从而破坏癌细胞中ATP的产生和氧的消耗。乳腺癌细胞系的体外研究以及已发表的数据表明,MCT4表达可能作为药物敏感性的生物标志物。值得注意的是,在细胞生长试验中,低MCT4表达与高效力相关。所鉴定的化合物表现出良好的药物样特性,包括良好的药代动力学和口服生物利用度。在两种低MCT4表达水平的乳腺癌模型中,每日口服剂量显著抑制肿瘤生长。然而,这种疗效伴随着体重的下降,需要通过优化或合理的联合治疗策略来提高治疗指标。这些发现强调了靶向线粒体OXPHOS在具有明确代谢依赖性的癌症中的治疗潜力,为利用肿瘤特异性代谢脆弱性改善癌症治疗提供了一种新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery and optimization of oxidative phosphorylation inhibitors from a phenotypic screen.

Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identification of novel, potent OXPHOS inhibitors. These lead compounds selectively target complex I of the mitochondrial electron transport chain, thereby disrupting ATP production and oxygen consumption in cancer cells. In-vitro studies in breast cancer cell lines, along with published data, suggest that MCT4 expression may serve as a biomarker for drug sensitivity. Notably, low MCT4 expression correlated with higher potency in cell growth assays. The identified compounds exhibited favorable drug-like properties, including good pharmacokinetics and oral bioavailability in mice. Daily oral dosing significantly inhibited tumor growth in two in-vivo breast cancer models with low MCT4 expression levels. This efficacy, however, was accompanied by body weight loss, indicating the need to enhance the therapeutic index through optimization or rational combination therapy strategies. These findings highlight the therapeutic potential of targeting mitochondrial OXPHOS in cancers with defined metabolic dependencies, offering a novel approach for exploiting tumor-specific metabolic vulnerabilities for improved cancer treatment.

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来源期刊
Anti-Cancer Drugs
Anti-Cancer Drugs 医学-药学
CiteScore
3.80
自引率
0.00%
发文量
244
审稿时长
3 months
期刊介绍: Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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