2. Academic Validation
  3. Identification of a new small Rho GTPase inhibitor effective in glioblastoma human cells

Identification of a new small Rho GTPase inhibitor effective in glioblastoma human cells

  • Eur J Med Chem. 2025 Aug 5:292:117704. doi: 10.1016/j.ejmech.2025.117704.
Angela Parise 1,  Ivana Manini 2,  Enrico Pobega 3,  Sonia Covaceuszach 4,  Luca Secco 3,  Federica Simonelli 1,  Serena Mastantuono 5,  Carla di Loreto 6,  Alessio Pizzignach 3,  Miran Skrap 7,  Marco Vindigni 7,  Riccardo Sgarra 3,  Guidalberto Manfioletti 3,  Daniela Cesselli 8,  Alessandra Magistrato 9
Affiliations

Affiliations

  • 1 Consiglio Nazionale delle Ricerche (CNR)-IOM, c/o International School for Advanced Studies (SISSA/ISAS), via Bonomia 265, 34136, Trieste, Italy.
  • 2 Institute of Pathology, University Hospital of Udine, 33100, Udine, Italy.
  • 3 Department of Life Sciences, University of Trieste, 34151, Trieste, Italy.
  • 4 Institute of Crystallography, National Research Council, Strada Statale 14 Km 16.5, Basovizza, 34149, (TS), Italy.
  • 5 Department of Medicine, University of Udine, 33100, Udine, Italy.
  • 6 Institute of Pathology, University Hospital of Udine, 33100, Udine, Italy; Department of Medicine, University of Udine, 33100, Udine, Italy.
  • 7 Neurosurgery Unit, Department of Neurosciences, University Hospital of Udine, 33100, Udine, Italy.
  • 8 Institute of Pathology, University Hospital of Udine, 33100, Udine, Italy; Department of Medicine, University of Udine, 33100, Udine, Italy. Electronic address: daniela.cesselli@uniud.it.
  • 9 Consiglio Nazionale delle Ricerche (CNR)-IOM, c/o International School for Advanced Studies (SISSA/ISAS), via Bonomia 265, 34136, Trieste, Italy. Electronic address: alessandra.magistrato@cnr.it.
PMID: 40334503 DOI: 10.1016/j.ejmech.2025.117704
Abstract

Glioblastoma (GBM) is the most common and lethal primary brain tumour. The prognosis for GBM patients remains poor due to rapid tumour recurrence and resistance to conventional treatments. Small Rho GTPase proteins, which regulate cell shape and motility, are critical for GBM aggressive growth and infiltration into the surrounding brain parenchyma. Hence, small-molecule inhibitors targeting them represent an appealing opportunity to hinder the infiltration behaviour of GBM. Here, a synergistic experimental and computational approach allowed us to identify an inhibitor that reduces migration in patient-derived GBM cell lines. Computational and in vitro functional assays reveal that this compound inhibits Rho GTPases function by targeting multiple allosteric sites thereby enhancing flexibility of key functional regions and hindering their interaction with protein regulators. Our research unveiled a novel hit molecule targeting Rho GTPases with significant potential to improve the treatment of GBM and Other highly aggressive tumours.

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