Details

Autor(en) / Beteiligte

• Chypre, Mélanie
• Madel, Maria-Bernadette
• Chaloin, Olivier
• Blin-Wakkach, Claudine
• Morice, Christophe
• Mueller, Christopher G

Titel

Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF-[kappa]B and Its Ligand

Ist Teil von

• ChemMedChem, 2017-10, Vol.12 (20), p.1697

Ort / Verlag

Weinheim: Wiley Subscription Services, Inc

Erscheinungsjahr

2017

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Receptor activator of NF-[kappa]B (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 pheophorbideA and purpurin18 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.