Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen.
The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2013
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| _version_ | 1797101115555184640 |
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| author | Simister, P Luccarelli, J Thompson, S Appella, D Feller, S Hamilton, A |
| author_facet | Simister, P Luccarelli, J Thompson, S Appella, D Feller, S Hamilton, A |
| author_sort | Simister, P |
| collection | OXFORD |
| description | The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 310 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface. |
| first_indexed | 2024-03-07T05:47:16Z |
| format | Journal article |
| id | oxford-uuid:e7a2fffb-433e-462f-b7f2-cd9659a1a4a5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:47:16Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:e7a2fffb-433e-462f-b7f2-cd9659a1a4a52022-03-27T10:40:23ZNovel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e7a2fffb-433e-462f-b7f2-cd9659a1a4a5EnglishSymplectic Elements at Oxford2013Simister, PLuccarelli, JThompson, SAppella, DFeller, SHamilton, AThe adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 310 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface. |
| spellingShingle | Simister, P Luccarelli, J Thompson, S Appella, D Feller, S Hamilton, A Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title | Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title_full | Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title_fullStr | Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title_full_unstemmed | Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title_short | Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. |
| title_sort | novel inhibitors of a grb2 sh3c domain interaction identified by a virtual screen |
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