Fiche publication
Date publication
octobre 2024
Journal
ChemMedChem
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DUBREZ Laurence
Tous les auteurs :
Farag MR, Guedeney N, Schwalen F, Zadorovnyj A, Barczyk A, Giret M, Antraygues K, Wang A, Cornu M, Suzanne P, Since M, Voisin-Chiret AS, Dubrez L, Leleu-Chavain N, Kieffer C, Sopkova-de Oliveira Santos J
Lien Pubmed
Résumé
The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20c. The ability of compound 20c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.
Mots clés
3D pharmacophore, Docking, Medicinal chemistry, XIAP inhibitor, fragment based drug design
Référence
ChemMedChem. 2024 10 4;:e202400567
