A Src SH2 selective binding compound inhibits osteoclast-mediated resorption.
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.
Violette
S M
SM
ARIAD Pharmaceuticals Inc., Biogen, Cambridge, Cambridge, MA 02139, USA. shelia_violette@biogen.com
Shakespeare
W C
WC
Bartlett
C
C
Guan
W
W
Smith
J A
JA
Rickles
R J
RJ
Bohacek
R S
RS
Holt
D A
DA
Baron
R
R
Sawyer
T K
TK
D000595:Amino Acid Sequence; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D001862:Bone Resorption / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014170:Transformation, Genetic; D020798:Two-Hybrid System Techniques; D018909:src Homology Domains / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001565:Benzoates; D004791:Enzyme Inhibitors; D008024:Ligands; D019061:src-Family Kinases; C409524:AP22161