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...
| Autors principals: | , , , , , |
|---|---|
| Format: | Journal article |
| Idioma: | English |
| Publicat: |
2013
|
| _version_ | 1826257844632027136 |
|---|---|
| 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 3 10 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 320 μM). 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. © 2013 Elsevier Ltd. All rights reserved. |
| first_indexed | 2024-03-06T18:24:37Z |
| format | Journal article |
| id | oxford-uuid:07839a53-1160-46b8-9aa0-ca3a2e20f528 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:24:37Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:07839a53-1160-46b8-9aa0-ca3a2e20f5282022-03-26T09:07:52ZNovel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screenJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:07839a53-1160-46b8-9aa0-ca3a2e20f528EnglishSymplectic 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 3 10 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 320 μM). 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. © 2013 Elsevier Ltd. All rights reserved. |
| 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 |
| work_keys_str_mv | AT simisterp novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen AT luccarellij novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen AT thompsons novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen AT appellad novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen AT fellers novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen AT hamiltona novelinhibitorsofagrb2sh3cdomaininteractionidentifiedbyavirtualscreen |