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Published on: January 1, 2017
A Src SH2 selective binding compound inhibits osteoclast-mediated resorption
S M Violette1, W C Shakespeare, C Bartlett
1ARIAD Pharmaceuticals Inc., Biogen, Cambridge, Cambridge, MA 02139, USA. shelia_violette@biogen.com
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.
Insights
A novel compound, AP22161, selectively inhibits the Src SH2 domain, effectively reducing osteoclast resorption. This discovery offers a promising therapeutic avenue for treating bone diseases like osteoporosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Src tyrosine kinase is implicated in osteoclast-resorptive activity, evidenced by osteopetrosis in Src(-/-) mice.
- Inhibitors of Src family tyrosine kinases reduce bone resorption mediated by osteoclasts.
Purpose of the Study:
- To design and synthesize a selective Src SH2 domain inhibitor.
- To evaluate the compound's efficacy in inhibiting Src-dependent cellular activity and osteoclast resorption.
Main Methods:
- Designed AP22161 to target a cysteine residue in the Src SH2 phosphotyrosine-binding pocket.
- Tested AP22161 in vitro for selective binding to the Src SH2 domain with high affinity.
- Assessed AP22161 in cellular assays for its ability to block Src SH2 binding and inhibit osteoclast activity.
Main Results:
- AP22161 demonstrated selective and high-affinity binding to the Src SH2 domain.
- The compound effectively blocked Src SH2 binding to peptide ligands in cellular assays.
- AP22161 significantly inhibited Src-dependent cellular activity and diminished osteoclast resorptive activity.
Conclusions:
- A compound selectively inhibiting Src SH2 binding can effectively reduce osteoclast resorption.
- AP22161 shows potential for development as a therapeutic agent for osteoporosis.
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