Cell reports. Medicine · 2025
A Rac-specific competitive inhibitor of guanine nucleotide binding reduces metastasis in triple-negative breast cancer.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Dilasser Florian, Rose Lindsay, Quemener Agnès, Ferrandez Yann, Hassoun Dorian, Rousselle Morgane, Bergereau Hugo, Lambot Séverine Marionneau, Anselmino Luciano E, Trouillet Camille, Andre Gwennan, Maillasson Mike, Croyal Mikael, Riviere Matthieu, Dubreuil Didier, Collet Sylvain, Souaze Frédérique, Campone Mario, Patsouris Anne, Mortier Erwan, Marquez Mauricio Menacho, Juin Philippe, Lebreton Jacques, Tessier Arnaud, Cherfils Jacqueline, Loirand Gervaise, Sauzeau Vincent
Аннотация
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.