Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells.
The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using hom...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC4287437?pdf=render |
| _version_ | 1819117412478353408 |
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| author | Lu Chen Lei Du-Cuny Sylvestor Moses Sabrina Dumas Zuohe Song Abdol Hossein Rezaeian Hui-Kuan Lin Emmanuelle J Meuillet Shuxing Zhang |
| author_facet | Lu Chen Lei Du-Cuny Sylvestor Moses Sabrina Dumas Zuohe Song Abdol Hossein Rezaeian Hui-Kuan Lin Emmanuelle J Meuillet Shuxing Zhang |
| author_sort | Lu Chen |
| collection | DOAJ |
| description | The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein. |
| first_indexed | 2024-12-22T05:32:34Z |
| format | Article |
| id | doaj.art-56c804a6540e4387827ecf871d75e93e |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-12-22T05:32:34Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-56c804a6540e4387827ecf871d75e93e2022-12-21T18:37:25ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582015-01-01111e100402110.1371/journal.pcbi.1004021Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells.Lu ChenLei Du-CunySylvestor MosesSabrina DumasZuohe SongAbdol Hossein RezaeianHui-Kuan LinEmmanuelle J MeuilletShuxing ZhangThe Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.http://europepmc.org/articles/PMC4287437?pdf=render |
| spellingShingle | Lu Chen Lei Du-Cuny Sylvestor Moses Sabrina Dumas Zuohe Song Abdol Hossein Rezaeian Hui-Kuan Lin Emmanuelle J Meuillet Shuxing Zhang Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. PLoS Computational Biology |
| title | Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. |
| title_full | Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. |
| title_fullStr | Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. |
| title_full_unstemmed | Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. |
| title_short | Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. |
| title_sort | novel inhibitors induce large conformational changes of gab1 pleckstrin homology domain and kill breast cancer cells |
| url | http://europepmc.org/articles/PMC4287437?pdf=render |
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