Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF-κB and Its Ligand

5 years ago

Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF-κB and Its Ligand

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

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. Pulling RANK: Receptor activator of NF-κB (RANK) plays a key role in bone resorption and stimulates immune and epithelial cell activation. A small-molecule inhibitor of the interaction between RANK and its ligand (RANKL) would facilitate treatments with orally available drugs. Herein we report the first nonpeptidic inhibitors of RANK–RANKL interactions. This discovery of a group of small molecules that block RANK activation provides an initial basis for further development of nonpeptidic agents that target the interaction between RANK and RANKL.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700462