دورية أكاديمية
Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption.
| العنوان: | Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption. |
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| المؤلفون: | Violette SM; ARIAD Pharmaceuticals Inc., Cambridge, MA 02139, USA., Guan W, Bartlett C, Smith JA, Bardelay C, Antoine E, Rickles RJ, Mandine E, van Schravendijk MR, Adams SE, Lynch BA, Shakespeare WC, Yang M, Jacobsen VA, Takeuchi CS, Macek KJ, Bohacek RS, Dalgarno DC, Weigele M, Lesuisse D, Sawyer TK, Baron R |
| المصدر: | Bone [Bone] 2001 Jan; Vol. 28 (1), pp. 54-64. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8504048 Publication Model: Print Cited Medium: Print ISSN: 8756-3282 (Print) Linking ISSN: 18732763 NLM ISO Abbreviation: Bone Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York : Elsevier Science Original Publication: Elmsford, NY : Pergamon Press, c1985- |
| مواضيع طبية MeSH: | Bone Resorption/*metabolism , Diphosphonates/*metabolism , Osteoclasts/*metabolism , src Homology Domains/*physiology , src-Family Kinases/*metabolism, Actins/metabolism ; Amino Acid Sequence ; Animals ; Cell Line, Transformed ; Dentin/metabolism ; Diphosphonates/chemistry ; Diphosphonates/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Fibroblasts/cytology ; Humans ; Ligands ; Mammals ; Mice ; Molecular Sequence Data ; Osteoclasts/cytology ; Osteoporosis/metabolism ; Rabbits ; Radioligand Assay ; Rats ; Tritium ; Two-Hybrid System Techniques ; src-Family Kinases/antagonists & inhibitors |
| مستخلص: | Src, a nonreceptor tyrosine kinase, is an important regulator of osteoclast-mediated resorption. We have investigated whether compounds that bind to the Src SH2 domain inhibit Src activity in cells and decrease osteoclast-mediated resorption. Compounds were examined for binding to the Src SH2 domain in vitro using a fluorescence polarization binding assay. Experiments were carried out with compounds demonstrating in vitro binding activity (nmol/L range) to determine if they inhibit Src SH2 binding and Src function in cells, demonstrate blockade of Src signaling, and lack cellular toxicity. Cell-based assays included: (1) a mammalian two-hybrid assay; (2) morphological reversion and growth inhibition of cSrcY527F-transformed cells; and (3) inhibition of cortactin phosphorylation in csk-/- cells. The Src SH2 binding compounds inhibit Src activity in all three of these mechanism-based assays. The compounds described were synthesized to contain nonhydrolyzable phosphotyrosine mimics that bind to bone. These compounds were further tested and found to inhibit rabbit osteoclast-mediated resorption of dentine. These results indicate that compounds that bind to the Src SH2 domain can inhibit Src activity in cells and inhibit osteoclast-mediated resorption. |
| المشرفين على المادة: | 0 (AP21946) 0 (AP22188) 0 (AP22408) 0 (AP22409) 0 (Actins) 0 (Diphosphonates) 0 (Enzyme Inhibitors) 0 (Ligands) 10028-17-8 (Tritium) EC 2.7.10.2 (src-Family Kinases) |
| تواريخ الأحداث: | Date Created: 20010213 Date Completed: 20010607 Latest Revision: 20190906 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1016/s8756-3282(00)00427-0 |
| PMID: | 11165943 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 8756-3282 |
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| DOI: | 10.1016/s8756-3282(00)00427-0 |