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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
Chemistry & Biology
|March 14, 2000
Summary
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.