Development of fluorizoline analogues as prohibitin ligands that modulate C-RAF signaling, p21 expression and melanogenesis.
Fiche publication
Date publication
août 2022
Journal
European journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent, Dr NEBIGIL-DESAUBRY Canan
Tous les auteurs :
Chouha N, Abou-Hamdan H, Yurugi H, Yoshii R, Ii H, Najem A, Ghanem GE, Nakata S, Rajalingam K, Peng Y, Wang D, Nebigil CG, Désaubry L
Lien Pubmed
Résumé
Fluorizoline is a cytotoxic trifluorothiazoline that targets the scaffold proteins prohibitins-1 and -2 (PHB1/2) to inhibit the kinase C-RAF and promote the expression of the cyclin-dependent kinase inhibitor p21 to induce cancer cell death. In melanocytes, fluorizoline also induces the synthesis of melanin. Herein we report the first structural requirement of fluorizoline analogues for these activities. We identified in particular some compounds that display enhanced anti-C-RAF and anti-MEK activities, and a higher cytotoxicity in HeLa cells compared to fluorizoline. These results provide a foundation for further optimization of PHB ligands for the treatment of cancers. We also discovered an analogue of fluorizoline that displays pharmacological effects opposed to those of fluorizoline and that can be used as a chemical tool to explore PHB signaling in cancers and other diseases.
Mots clés
Cancer, Heterocycles, MAP kinases, Melanogenesis, Prohibitins, p21
Référence
Eur J Med Chem. 2022 08 4;242:114635