Fiche publication
Date publication
octobre 2017
Journal
ChemMedChem
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MUELLER Christopher
Tous les auteurs :
Chypre M, Madel MB, Chaloin O, Blin-Wakkach C, Morice C, Mueller CG
Lien Pubmed
Résumé
Receptor activator of NF-κB (RANK), a member of the TNF-receptor superfamily, plays an important role in bone resorption and stimulates immune and epithelial cell activation. Denosumab, a human monoclonal antibody that blocks the RANK ligand (RANKL), is approved for the treatment of osteoporosis and bone metastasis. However, a small molecule that inhibits the RANK-RANKL interaction would be beneficial to decrease cost and to facilitate treatments with orally available therapeutic agents. Herein we report the discovery of the first nonpeptidic inhibitors of RANK-RANKL interactions. In screening a chemical library by competitive ELISA, the porphyrin verteporfin was identified as a hit. Derivatives were screened, and the chlorin-macrocycle-containing pheophorbide A and purpurin 18 were found to bind recombinant RANKL, to inhibit RANK-RANKL interactions in the ELISA, and to suppress the RANKL-dependent activation of model cells and the differentiation of RANK-expressing precursors into osteoclasts. This discovery of a family of small molecules that inhibit RANK activation presents an initial basis for further development of nonpeptidic therapeutic agents targeting the interaction between RANK and RANKL.
Mots clés
ELISA, cell-based assays, osteoclasts, porphyrins, receptor activator of NF-κB
Référence
ChemMedChem. 2017 10 20;12(20):1697-1702
