Fragment-based drug design targeting syntenin PDZ2 domain involved in exosomal release and tumour spread - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2021

Fragment-based drug design targeting syntenin PDZ2 domain involved in exosomal release and tumour spread

Résumé

Syntenin stimulates exosome production and its expression is upregulated in many cancers and implicated in the spread of metastatic tumor. These effects are supported by syntenin PDZ domains interacting with syndecans. We therefore aimed to develop, through a fragment-based drug design approach, novel inhibitors targeting syntenin-syndecan interactions. We describe here the optimization of a fragment, ‘hit’ C58, identified by in vitro screening of a PDZ-focused fragment library, which binds specifically to the syntenin-PDZ2 domain at the same binding site as the syndecan-2 peptide. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 45 and 57 (IC50 = 33 μM and 47 μM; respectively), two representatives of syntenin-syndecan interactions inhibitors, that selectively affect the syntenin-exosome release. These findings demonstrate that it is possible to identify small molecules inhibiting syntenin-syndecan interaction and exosome release that may be useful for cancer therapy.
Fichier principal
Vignette du fichier
EJMCh_Barral_2021_27052021.pdf (689.24 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03379016 , version 1 (15-10-2021)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

Manon Garcia, Laurent Hoffer, Raphaël Leblanc, Fatiha Benmansour, Mikael Feracci, et al.. Fragment-based drug design targeting syntenin PDZ2 domain involved in exosomal release and tumour spread. European Journal of Medicinal Chemistry, 2021, 223, pp.113601. ⟨10.1016/j.ejmech.2021.113601⟩. ⟨hal-03379016⟩
69 Consultations
46 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More