Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-κB Ligand (RANKL)Receptor Activator of Nuclear Factor-κB (RANK) Protein–Protein Interaction by Structure-Based Virtual Screening and Hit Optimization

Targeting
RANKL/RANK offers the possibility of developing novel
therapeutic approaches to treat bone metabolic diseases. Multiple
efforts have been made to inhibit RANKL. For example, marketed monoclonal
antibody drug Denosumab could inhibit the maturation of osteoclasts
by binding to RANKL. This study is an original approach aimed at discovering
small-molecule inhibitors impeding RANKL/RANK protein interaction.
We identified compound 34 as a potent and selective RANKL/RANK
inhibitor by performing structure-based virtual screening and hit
optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption.
The expression of osteoclast marker genes was also suppressed by treatment
of 34. Furthermore, 34 markedly blocked
the NFATc1/c-fos pathway. Thus, our current work demonstrates that
the chemical tractability of the difficult PPI (RANKL/RANK) target
by a small-molecule compound 34 offers a potential lead
compound to facilitate the development of new medications for bone-related
diseases.