A Src SH2 selective binding compound inhibits osteoclast-mediated resorption

Background: The observations that Src(-/-) mice develop osteopetrosis and S rc family tyrosine kinase inhibitors decrease osteoclast-mediated resorptio n of bone have implicated Src in the regulation of osteoclast-resorptive ac tivity. We have designed and synthesized a compound, AP22161, that binds se lectively to the Src SH2 domain and demonstrated that it inhibits Src-depen dent cellular activity and inhibits osteoclast-mediated resorption. Results: AP22161 was designed to bind selectively to the Src SH2 domain by targeting a cysteine residue within the highly conserved phosphotyrosine-bi nding pocket. AP22161 was tested in vitro for binding to SH2 domains and wa s found to bind selectively and with high affinity to the Src SH2 domain. A P22161 was further tested in mechanism-based cellular assays and found to b lock Src SH2 binding to peptide ligands, inhibit Src-dependent cellular act ivity and diminish osteoclast resorptive activity. Conclusions: These results indicate that a compound that selectively inhibi ts Src SH2 binding can be used to inhibit osteoclast resorption. Furthermor e, AP22161 has the potential to be further developed for treating osteoporo sis.