BACKGROUND: The observations that Src(-/-) mice develop osteopetrosis and Src family tyrosine kinase inhibitors decrease osteoclast-mediated resorption of bone have implicated Src in the regulation of osteoclast-resorptive activity. We have designed and synthesized a compound, AP22161, that binds selectively to the Src SH2 domain and demonstrated that it inhibits Src-dependent 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-binding pocket. AP22161 was tested in vitro for binding to SH2 domains and was found to bind selectively and with high affinity to the Src SH2 domain. AP22161 was further tested in mechanism-based cellular assays and found to block Src SH2 binding to peptide ligands, inhibit Src-dependent cellular activity and diminish osteoclast resorptive activity. CONCLUSIONS: These results indicate that a compound that selectively inhibits Src SH2 binding can be used to inhibit osteoclast resorption. Furthermore, AP22161 has the potential to be further developed for treating osteoporosis.
BACKGROUND: The observations that Src(-/-) mice develop osteopetrosis and Src family tyrosine kinase inhibitors decrease osteoclast-mediated resorption of bone have implicated Src in the regulation of osteoclast-resorptive activity. We have designed and synthesized a compound, AP22161, that binds selectively to the Src SH2 domain and demonstrated that it inhibits Src-dependent 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-binding pocket. AP22161 was tested in vitro for binding to SH2 domains and was found to bind selectively and with high affinity to the Src SH2 domain. AP22161 was further tested in mechanism-based cellular assays and found to block Src SH2 binding to peptide ligands, inhibit Src-dependent cellular activity and diminish osteoclast resorptive activity. CONCLUSIONS: These results indicate that a compound that selectively inhibits Src SH2 binding can be used to inhibit osteoclast resorption. Furthermore, AP22161 has the potential to be further developed for treating osteoporosis.
Authors: Pijus K Mandal; Donald Limbrick; David R Coleman; Garrett A Dyer; Zhiyong Ren; J Sanderson Birtwistle; Chiyi Xiong; Xiaomin Chen; James M Briggs; John S McMurray Journal: J Med Chem Date: 2009-04-23 Impact factor: 7.446
Authors: W Shakespeare; M Yang; R Bohacek; F Cerasoli; K Stebbins; R Sundaramoorthi; M Azimioara; C Vu; S Pradeepan; C Metcalf; C Haraldson; T Merry; D Dalgarno; S Narula; M Hatada; X Lu; M R van Schravendijk; S Adams; S Violette; J Smith; W Guan; C Bartlett; J Herson; J Iuliucci; M Weigele; T Sawyer Journal: Proc Natl Acad Sci U S A Date: 2000-08-15 Impact factor: 11.205
Authors: Ywh-Min Tzou; Sarah K Bailey; Kaiyu Yuan; Ronald Shin; Wei Zhang; Yabing Chen; Raj K Singh; Lalita A Shevde; N Rama Krishna Journal: Bioorg Med Chem Lett Date: 2016-01-12 Impact factor: 2.823