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

  • Cell Rep Med. 2025 Jul 15;6(7):102233. doi: 10.1016/j.xcrm.2025.102233.
Florian Dilasser  1 ,  Lindsay Rose  1 ,  Agnès Quemener  2 ,  Yann Ferrandez  3 ,  Dorian Hassoun  1 ,  Morgane Rousselle  1 ,  Hugo Bergereau  1 ,  Séverine Marionneau Lambot  2 ,  Luciano E Anselmino  4 ,  Camille Trouillet  5 ,  Gwennan Andre  1 ,  Mike Maillasson  6 ,  Mikael Croyal  7 ,  Matthieu Riviere  5 ,  Didier Dubreuil  5 ,  Sylvain Collet  5 ,  Frédérique Souaze  2 ,  Mario Campone  2 ,  Anne Patsouris  2 ,  Erwan Mortier  6 ,  Mauricio Menacho Marquez  4 ,  Philippe Juin  2 ,  Jacques Lebreton  5 ,  Arnaud Tessier  5 ,  Jacqueline Cherfils  3 ,  Gervaise Loirand  8 ,  Vincent Sauzeau  9
Affiliations
  • 1. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France.
  • 2. Nantes Université, Inserm, CNRS, CRCI(2)NA, Nantes F-44000, France.
  • 3. Laboratory of biology and applied pharmacology, CNRS, ENS Paris-Saclay, Paris, France.
  • 4. Instituto de Inmunología Clínica y Experimental de Rosario (IDICER CONICET-UNR), Centro de Investigación del Cáncer de Rosario. Facultad de Ciencias Médicas, Rosario, Santa Fe 3100, Argentina.
  • 5. Nantes Université, CNRS, CEISAM, UMR 6230, Nantes F-44000, France.
  • 6. Nantes Université, Inserm, CNRS, CRCI(2)NA, Nantes F-44000, France; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, Nantes, France.
  • 7. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, Nantes, France.
  • 8. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France. Electronic address: [email protected].
  • 9. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France. Electronic address: [email protected].
PMID: 40633540 DOI: 10.1016/j.xcrm.2025.102233
Abstract

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.

Keywords
RAC1; drug discovery; invasive cancer; triple-negative breast cancer.
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