RRC ID 72663
Author 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.
Title Development of fluorizoline analogues as prohibitin ligands that modulate C-RAF signaling, p21 expression and melanogenesis.
Journal Eur J Med Chem
Abstract 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.
Volume 242
Pages 114635
Published 2022-11-15
DOI 10.1016/j.ejmech.2022.114635
PII S0223-5234(22)00537-2
PMID 35988448
MeSH Apoptosis* Cyclin-Dependent Kinase Inhibitor p21 / metabolism HeLa Cells Humans Ligands Melanins / metabolism Prohibitins* Protein Serine-Threonine Kinases Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-raf / metabolism Proto-Oncogene Proteins c-raf / pharmacology Repressor Proteins Transcription Factors / metabolism
IF 5.573
Human and Animal Cells MCF7(RCB1904)