6533b824fe1ef96bd1280c27

RESEARCH PRODUCT

Molecular Mechanisms of the Blockage of Glioblastoma Motility

Angelo SpinelloXiaoyun LiVincent TorreSara LaporteAlessandra MagistratoFederica SimonelliJing Xu

subject

rac1 GTP-Binding Proteinrho GTP-Binding ProteinsGeneral Chemical EngineeringBrain tumorMotilityRAC1CDC42Library and Information SciencesBiologySettore BIO/09 - FisiologiaMicrotubules01 natural sciencesDownregulation and upregulationLive cell imaging0103 physical sciencesmedicineHumanscdc42 GTP-Binding Protein010304 chemical physicsDrug discoveryCancerGeneral Chemistrymedicine.disease0104 chemical sciencesComputer Science Applications010404 medicinal & biomolecular chemistrySettore CHIM/03 - Chimica Generale E InorganicaCancer researchGlioblastoma

description

Glioblastoma (GBM) is the most common and lethal brain tumor. GBM has a remarkable degree of motility and is able to infiltrate the healthy brain. In order to perform a rationale-based drug-repositioning study, we have used known inhibitors of two small Rho GTPases, Rac1 and Cdc42, which are upregulated in GBM and are involved in the signaling processes underlying the orchestration of the cytoskeleton and cellular motility. The selected inhibitors (R-ketorolac and ML141 for Cdc42 and R-ketorolac and EHT 1864 for Rac1) have been successfully employed to reduce the infiltration propensity of GBM in live cell imaging studies. Complementarily, all-atom simulations have elucidated the molecular basis of their inhibition mechanism, identifying the binding sites targeted by the inhibitors and dissecting their impact on the small Rho GTPases' function. Our results demonstrate the potential of targeting the Rac1 and Cdc42 proteins with small molecules to contrast GBM infiltration growth and supply precious information for future drug discovery studies aiming to fight GBM and other infiltrative cancer types.

yearjournalcountryeditionlanguage
2021-04-16Journal of Chemical Information and Modeling
https://doi.org/10.1021/acs.jcim.1c00279