一种rac特异性的鸟嘌呤核苷酸结合竞争性抑制剂可减少三阴性乳腺癌的转移。

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-07-15 Epub Date: 2025-07-08 DOI:10.1016/j.xcrm.2025.102233

Florian Dilasser, Lindsay Rose, Agnès Quemener, Yann Ferrandez, Dorian Hassoun, Morgane Rousselle, Hugo Bergereau, Séverine Marionneau Lambot, Luciano E Anselmino, Camille Trouillet, Gwennan Andre, Mike Maillasson, Mikael Croyal, Matthieu Riviere, Didier Dubreuil, Sylvain Collet, Frédérique Souaze, Mario Campone, Anne Patsouris, Erwan Mortier, Mauricio Menacho Marquez, Philippe Juin, Jacques Lebreton, Arnaud Tessier, Jacqueline Cherfils, Gervaise Loirand, Vincent Sauzeau

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引用次数: 0

摘要

在一些癌症中，RAC1活性的失调与肿瘤转化、转移和不良预后有关。在这里，我们在硅中发现了一系列的RAC1抑制剂。其中最有效的是A41，它以一种原始的作用机制特异性抑制RAC1。我们将A41描述为一种可逆抑制剂，与鸟嘌呤核苷酸结合特异性地与RAC蛋白竞争。A41有效阻断RAC1活性和依赖于RAC1的细胞功能，包括细胞粘附和迁移。慢性给药A41在三阴性乳腺癌小鼠模型中表现出抗转移作用，导致生存率增加。我们的研究结果表明，这种分子A41可能是一种有前途的、强大的治疗药物，可以限制患者的侵袭性癌症。

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A Rac-specific competitive inhibitor of guanine nucleotide binding reduces metastasis in triple-negative breast cancer.

The dysregulation of RAC1 activity is associated with neoplastic transformation, metastasis, and poor prognosis in several cancers. Here, we discover in silico a series of RAC1 inhibitors. The most potent of them, A41, specifically inhibits RAC1 with an original mechanism of action. We characterize A41 as a reversible inhibitor that competes with guanine nucleotide binding specifically on RAC proteins. A41 efficiently blocks RAC1 activity and RAC1-dependent cell functions including cell adhesion and migration. Chronic administration of A41 exhibits anti-metastatic effects in mouse models of triple-negative breast cancer, leading to an increase in the survival rate. Our findings suggest that this molecule, A41, could be a promising and powerful therapeutic agent for limiting invasive cancers in patients.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.